Kinetica User Manual

Kinetica 5.
0
Kinetica User Manual
© 2005–2008 Thermo Fisher Scientific Inc. All rights reserved.
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Part Number KIN-UM-5.0
Revision Number 1.00
Software Version Kinetica 5.0
Thermo Fisher Scientific Kinetica User Manual i

Notes
ii Kinetica User Manual Thermo Fisher Scientific

Contents
1. Introduction and Configuration .............................................. 1
Kinetica Documentation..................................................... 2
Understanding Kinetica Basic Concepts.............................. 3
Kinetica Templates ............................................................. 4
Kinetica Methods................................................................ 6
Configuring Kinetica .......................................................... 7
Setting up Reports .............................................................. 8
Configuring Print Setup.................................................... 12
2. Starting Kinetica.................................................................... 13
Using the Kinetica Workspace .......................................... 14
Kinetica Main Menu......................................................... 16
Kinetica Toolbar ............................................................... 41
Kinetica Views .................................................................. 45
Kinetica Status Bar............................................................ 51
Kinetica Spreadsheet Interface........................................... 52
Kinetica Default Data Structure........................................ 61
3. Opening and Saving Data Files ............................................ 63
Files in Kinetica ................................................................ 64
Opening an Existing Kinetica File..................................... 65
Customizing the Normal Kinetica Template..................... 66
Opening an Existing Kinetica Template............................ 68
Saving Kinetica Files ......................................................... 70
4. Unit Configuration in Kinetica .............................................. 73
Configuring Units............................................................. 74
Specifying Units................................................................ 75
Specifying Concentration Units ........................................ 76
Specifying Column Units.................................................. 80
Specifying Rate Units........................................................ 82
Getting Units.................................................................... 85
Multiplying Units ............................................................. 87
Specifying Molar Units for the AUC* Method.................. 93
Thermo Fisher Scientific Kinetica User Manual iii

Contents
5. Importing and Exporting Data ............................................... 97

Intelligent Spreadsheet and Intelligent Import...................98
Importing Files into Kinetica with Import Assistant ........104
Using the Import Assistant Wizard..................................105
Importing Data from Excel Spreadsheets .........................107
Importing Data from ASCII Files....................................128
Importing Data from Databases ......................................142
Importing Data in Proprietary Formats ...........................156
Importing Data from Watson LIMS................................162
Importing Miscellaneous Data.........................................165
Exporting Data to External Databases .............................168
Report Log Files ..............................................................172
6. Graphs in Kinetica ............................................................... 175
Working with Graphs......................................................176
Starting the Chart Wizard ...............................................177
Hot Graphs .....................................................................191
Dataset Graph .................................................................192
Spaghetti Plot ..................................................................196
LZ Graph ........................................................................198
Mean Curve ....................................................................199
Plotting a Graph Manually ..............................................210
Plotting a Graph Automatically .......................................212
Inserting a Graph Method ...............................................214
Modifying Graphs ...........................................................218
Displaying Outlier Data ..................................................220
Displaying Non-Detectable Data Points..........................223
Mean Curve by Group Method.......................................226
Creating Graph Templates ..............................................230
Working with the Graph Gallery.....................................233
Exporting Graphs ............................................................243
Linear Regression ............................................................245
Linear Regression with CI ...............................................248
Mean Curve Statistics ......................................................249
Histogram Statistics.........................................................250
Scattered XY Plot (Numeric X-Axis) Plotting ..................254
Scattered XY Plot (Textual X-Axis) Plotting ....................255
iv Kinetica User Manual Thermo Fisher Scientific

Contents
7. Methods and Models .......................................................... 257

Working with Methods and Models in Kinetica ............. 258
Area Under the Curve (AUC) Calculation Methods ....... 264
AUC Steady State* Methods ........................................... 284
Sparse AUC Method....................................................... 286
Superposition–Variable Dosage Method ......................... 287
Convolution Method ...................................................... 290
Deconvolution Method................................................... 293
Derivation Method ......................................................... 296
Linear Regression by Zero Method ................................. 298
Macro to Micro Method ................................................. 299
Micro to Macro Method ................................................. 302
tN% Method .................................................................. 305
tN% of Cmax Method.................................................... 306
Kinetica Method Editor .................................................. 307
Opening Methods/Models .............................................. 308
Kinetica Designer............................................................ 311
Designer Dialog .............................................................. 312
Link Types...................................................................... 317
Available Tool Operations............................................... 319
Example of a Designer Method ....................................... 324
Using Designer to Generate a Differential Equation ....... 325
8. Non-Compartmental Analysis ............................................ 327
Performing Non-Compartmental Analysis in Kinetica .... 328
The AUC* Method......................................................... 329
Built-in templates for NCA............................................. 336
IV Bolus Template.......................................................... 337
IV Infusion Template...................................................... 350
Extravascular Route Template......................................... 360
Summary of First Dose PK Parameters for each
Administration Route ..................................................... 367
Steady State Template..................................................... 369
The AUC steady-state with Lz* and AUC steady-state*
Methods.......................................................................... 383
The Sparse AUC* Method .............................................. 390
The Superposition – Variable Dosage Method ................ 397
Working with the NCA Assistant.................................... 402
Flagging Data as BLQ (Undetectable)............................. 410
Thermo Fisher Scientific Kinetica User Manual v

Contents
9. Performing Compartmental Analysis ................................. 419

Fitting Data with Kinetica - Single Dose .........................420
Fitting Data with Kinetica - Multiple Dose .....................424
Available Models .............................................................429
Selecting a Method Model...............................................439
Initial Parameter Estimates ..............................................440
Stripping Algorithm ........................................................441
Weighting Schemes .........................................................442
Minimization Algorithm .................................................443
Differential Equation Solver ............................................444
Statistics and Goodness of Fit ..........................................445
PK Template Examples ...................................................449
Single Dose Zero Order Input Macro Constants Template
........................................................................................451
Single Dose IV Bolus Macro Constants Template ...........460
Single Dose IV Infusion Macro Constants Template.......464
Single Dose Zero Order Input Micro Constants Template
........................................................................................467
Single Dose Extravascular Micro Constants Template .....470
Single Dose IV Bolus Micro Constants Template............474
Single Dose IV Infusion Micro Constants Template .......477
Multiple Dose Extravascular Micro Constants Template .481
Multiple Dose IV Bolus Micro Constants Template........485
Multiple Dose IV Infusion Micro Constants Template ...490
Multiple Dose Multi Route Template .............................496
Performing PD Analysis ..................................................502
Performing PK/PD Analysis ............................................513
PK/PD Extravascular Template .......................................517
PK/PD IV Bolus Template..............................................529
PK/PD IV Infusion Template .........................................539
10. Creating Tables and Scripts ............................................... 549
Creating Tables and Scripts using the Table Assistant......550
Table Assistant Wizard ....................................................551
Regenerating Embedded Tables from Script Files ............573
Deleting a Table Script....................................................574
vi Kinetica User Manual Thermo Fisher Scientific

Contents
11. Population Pharmacokinetics (PK) .................................... 575

Introduction to Population PK Analysis in Kinetica........ 576
Features of Population PK Analysis in Kinetica ............... 578
Kinetica Population PK/PD Methods ............................. 582
Inserting a Population PK/PD Method........................... 586
Modifying Global Options.............................................. 589
Routes of Administration ................................................ 591
Kinetica Population Output Columns ............................ 597
Kinetica Population Templates ....................................... 598
Performing Advanced Fitting .......................................... 625
Working with Kinetica Population Graphs ..................... 627
Population Method Validation........................................ 636
Working with Population Designer................................. 652
Exporting Data to Microsoft Word................................. 654
12. Performing Statistical Analysis.......................................... 657
Statistical Analysis in Kinetica ......................................... 658
ANOVA ......................................................................... 659
Latin Square.................................................................... 673
Incomplete Block ............................................................ 697
Kruskall-Wallis Test........................................................ 703
Friedman Test................................................................. 707
Descriptive Statistics ....................................................... 710
The Paired and Unpaired t Test ...................................... 715
A. Population Methodology..................................................... 719
Models and Notation ...................................................... 720
Population Parameter Estimates - Sparse Data Situation . 722
Initial Parameter Estimates.............................................. 728
Minimization Algorithm ................................................. 733
Termination Criteria of EM Algorithm........................... 735
Differential Equation Solver............................................ 736
Stepwise Method............................................................. 737
Population Hard-Coded Equations................................. 739
References ....................................................................... 740
B. Kinetica Population Method Writing ................................. 743
OSMacro2compBasic ..................................................... 744
Multiple Dose Example................................................... 746
IV RungeKuttaMultidose................................................ 748
Index..................................................................................... 751
Thermo Fisher Scientific Kinetica User Manual vii

Notes
viii Kinetica User Manual Thermo Fisher Scientific

1. Introduction and
Configuration
Welcome to Kinetica, a powerful industry-standard
pharmacokinetic-pharmacodynamic (PK/PD) template and
method-driven system that enables you to standardize your
laboratory analyses. Kinetica has an intuitive point-and-click
graphical interface that facilitates data analysis and reporting in a
structured yet flexible, easy-to-automate environment.
Each Kinetica analysis is comprised of results computed using

either the default validated methods or customized
methodologies. Once specified, the Kinetica spreadsheet
containing the columns of methods can be saved as a template
and automatically applied to any other study. This offers an
efficient means of providing standardization across your
organization.
From non-compartmental to population PK/PD analyses,

Kinetica facilitates data analysis and reporting in a flexible
environment. Kinetica offers fast, high-throughput data analysis
for discovery, preclinical, clinical, drug metabolism and drug
delivery settings. Kinetica streamlines your data analysis process
by reducing the need for multiple software packages and
associated training.
Thermo Fisher Scientific Kinetica User Manual 1

Introduction and Configuration
Kinetica In addition to this user guide, your Kinetica package also contains
the following documentation:
Documentation
• The Kinetica Installation Guide instructs administrators how
to install, configure, and maintain Kinetica.
• The Kinetica Basic Reference Guide, a self-contained manual

for the Kinetica-specific Visual Basic-based scripting language
you may use to write your own methods.
This user guide is also available in WinHelp format; access it by

selecting Help on the Kinetica toolbar.
2 Kinetica User Manual Thermo Fisher Scientific

Understanding Kinetica is a template-driven system that provides standardized

pharmacokinetic-pharmacodynamic analysis for drug
Kinetica Basic development across your organization. The template design
Concepts allows you to reuse analysis settings, enabling you to maintain
consistency among analysts and analyses.
The organization of Kinetica templates and methods is made

through a single document interface consisting of a series of
panes, spreadsheets, graphical and web views. In addition,
Kinetica offers numerous statistical tests for bioequivalence
studies that are compliant with FDA, EMEA and MHW
regulatory guidelines.

Kinetica Templates A template is a collection of methods created and saved as an

empty shell for future analysis. Kinetica is delivered with over 50
different analytical template samples. In addition, you can create
as many templates as you need by modifying the templates
provided with the application.
Kinetica templates offer several advantages:
• High consistency between analyses and between users.
• Time savings by not having to validate each user’s analysis.
• Version control between analyses of the same study.
Kinetica is installed with nine subdirectories containing validated

templates that provide unique non-compartmental assistant
technology and a multitude of different standard and advanced
PK, PD and PK/PD models that offer the best in high-
throughput data analysis Templates are available for use with the
following types of kinetic analyses:
• Absorption Kinetics
• Compartmental Fitting
• Convolution/Deconvolution
• Enzyme Kinematics
• In Vivo/In Vitro Correlation
• Non-Compartmental Analyses
• Population Pharmacokinetics
• Protein Binding
• Urine Pharmacokinetics
Some of the templates that were previously accessed from the

New Analysis dialog are now located in the subdirectories of
‘Program Files\Kinetica\Example,’ as follows:

• Fitting Simulation
IVInfusion.kdb
• In Vitro Dissolution
Dissolution Basic.kdb
Dissolution with Volume Correction.kdb
Dissolution without Volume Correction.kdb
• In Vitro/In Vivo Correlation
In Vitro/In Vivo.kdb
• Michaelis-Menton
MM Extravascular 1 Comp.kdb
MM IVBolus 1 Comp.kdb
• Statistics
Anova.kdb
Descriptive Statistics.kdb
Group Table.kdb
Kruskall Wallis.kdb
Latin Square 2 Formulations.kdb
Latin Square Multiple Formulations.kdb
Latin Square N Formulations.kdb
Linear Regression.kdb
Unbalanced Block.kdb
• Transdermal
Transdermal Bioavailability.kdb
Transdermal Feasibility.kdb

Kinetica Methods A method is a default or user-defined calculation, which

computes values from existing columns of information.
Calculations are performed regardless of whether the existing
columns contain raw data or data computed using other methods.
If you save the dataset, Kinetica saves the results and the
method(s) in its proprietary database called KDB, in a file with a
.kdb extension. If you save the dataset as a template, Kinetica
deletes all data in all columns but embeds the method(s) in a
database as a template file with a .ktp extension. This template
file is then available for future use with other experimental data.
Method output columns have headings in blue.
Kinetica provides a library of pre-defined methods and models

covering the most appropriate functions. For more information,
see the chapter, “Working with Methods and Models.” Other
methods and models can be created with the macro language
provided called Kinetica Basic. This language is a subset of Visual
Basic for Applications (VBA) which is the same language used in
Microsoft Excel, Word and Access. For more information, see the
chapter, “Kinetica Method Editor,” and Appendix C.

Configuring Kinetica Once you have successfully installed Kinetica, some settings must
be configured in order for the program to run efficiently. You are
encouraged to follow these instructions to ensure that Kinetica
performs as you expect.

Setting up Reports During analysis various information is calculated, messages are

displayed, and errors are generated. In order to help Kinetica
handle this information, you need to dictate how the application
should operate. The Report Setup utility allows you to specify the
default destination for report-type output files. You only need to
do this once after you have installed Kinetica
Report Setup Report Setup is accessed from Kinetica’s File menu. The Report
Setup dialog contains two areas: Select Output and Double Click
to Set Destination.
Figure 1-1. Report Setup Dialog, Sample Configuration
The different report types available in Kinetica (as shown in

Select Output) are summarized in the table below.
Output Use in Kinetica
Report Automatically-generated text summary of methods

used during analysis, options chosen for the
methods, and the results computed during the
analysis, i.e., initial parameters, statistics on
goodness of fit, transformation of AUC calculations,
variance-covariance matrix, etc.

Output Use in Kinetica
Error Short text output altering you to errors encountered

during program execution.
Message Messages are generally warnings generated during

normal program use.
Table Table output is only generated via user interaction.

The user must select Kinetica information stored in
tables (arrays or grids) and can choose to send it to
Excel or delimited text files. It can include any
Kinetica information.
For each output option, you have several choices for the output
destination. Click once on the appropriate output, e.g. Report.
Double-click on the Destination you require, or select it once
with the mouse and click Set Destination. Destinations are
described in the table below.
Destination Destination Action
Text file Writes the selected output to a text file. You are
prompted to save the file as Repo.txt in the
\Kinetica\odriver sub-directory. You can name
the file as required, and store it in any directory
on the local or network drive. If you store the file
on a network drive, ensure that Kinetica has
access to the file at all times. This option is
recommended for Report output but not for
Error or Message outputs.
Message Displays the selected output in a message box.

Box This option is recommended for the Error or
Message outputs but not for the Report output.
Nothing Does not display or write any information.

Available as an option but is not recommended
for any output because you will not see any
information during an analysis.

Word 6/95 Links the Report output type to Microsoft Word.

document You are prompted to save the file as Report.doc
(version 6.0 or 95 only) in the \Kinetica\odriver
directory. You can name the file as required and
store it in any directory on the local or network
drive. If you store the file on a network drive,
ensure that Kinetica has access to the file at all
times.
This option does not automatically load

Microsoft Word when you run an analysis or
click on the export icon within Kinetica. Open
Word before executing an analysis if you want to
see your report automatically written to Word.
Word 97 Links the Report output type to Microsoft Word

document version 97. You are prompted to save the file as
Report.doc (version 97 only) in the
the file as required and store it in any directory
access to the file at all times.
This option automatically finds, and then loads

click on the Word export icon within Kinetica.
The report is then automatically written to
Word.

Graph for Links all Graph output to Microsoft Word

Word 97 version 97. You are prompted to save the file as
document Repo.doc (version 97 only) in the
the file as required and store it in any directory
access to the file at all times.
This option automatically finds, and then loads

click on the Word export icon within Kinetica
and sends all plotted graphs to Word. No other
text information is sent to Word with these
graphs.
Excel Links the Table Assistant or Data export output

type to Microsoft Excel. You are prompted to
save the file as Tabl.xls in the \Kinetica\odriver
sub-directory. You can name the file as required
and store it in any directory on the local or
network drive. If you store the file on a network
drive, ensure that Kinetica has access to the file at
all times.
This option automatically finds and loads

Microsoft Excel when you create structured
tables using Table Assistant.
Note This option is only active when the

output is set to “table.” ▲

Configuring Print The appearance of the Print Setup dialog differs according to the
system and printer you are using. Microsoft Windows controls
Setup the dialog displayed for your particular system. Please refer to
your Microsoft Windows documentation for assistance with
printer setup.

2. Starting Kinetica
This chapter provides information on starting the Kinetica
application. Also included is information on the various Kinetica
commands, views, toolbar options, and spreadsheet interfaces, as
well as the default Kinetica data structure.

Starting Kinetica
Using the Kinetica When you first open Kinetica, the Welcome dialog appears.
Click Cancel and the Workspace appears. The Workspace
Workspace comprises a main menu, toolbar, left pane, and spreadsheet
interface.
The Workspace is organized as a series of spreadsheets, graphical

and web views. These views, in conjunction with the main menu,
toolbar and left pane, allow you to apply methods, run analyses,
produce tables, and create and organize graphs.
Figure 2-1. Kinetica Workspace, Dataset pane
Kinetica has a structure similar to that of a database; it has various

interrelated tables, unlike a flat spreadsheet. Due to this design,
there is hierarchy in the Kinetica data file. Worksheet columns in
the Dataset pane (see figure above) are at the bottom of the
hierarchy. They are placeholders for non-static time-series data,
such as individual time-concentration data. Datasets can be
viewed one at a time. To view another dataset, use the X icon on

Starting Kinetica
the toolbar to move forward one dataset or the W icon to move

backward.
The second level in the Kinetica structure contains the dataset

variables under the Study pane. Dataset variables are unique to
the individual datasets, i.e., each cell takes only one value for that
individual. For example, the pharmacokinetic parameter Cmax is
a unique value since for each analysis run only one Cmax value
for that individual is generated. The dataset variable often
contains the pharmacokinetic results generated from a non-
compartmental analysis method.
The highest level in the hierarchy is the global variables level, also
under the Study pane. Population mean and Variance from a
population pharmacokinetic analysis are both global variables.
This level is not often used as most analyses deal with individuals
rather than an entire study.

Starting Kinetica
Kinetica Main Menu The Kinetica main menu bar is located at the top of the Kinetica
workspace. The menu commands are described in the table
below.
Option Description
File Access options for file manipulation, printing

and default program setup parameters, open
and save galleries, export data to Microsoft
Word or Excel, or exit Kinetica.
Edit Access options for editing and/or removing

fields and methods from the current dataset
or template. You can also search and replace
specified text.
View Access options for customizing toolbars and

commands, displaying toolbars, properties,
headers and footers, zoom in or out.
Insert Access options for inserting fields and/or

methods into the current dataset or template.
Format Access options for changing the way the

program displays spreadsheets.
Dataset Access options for scrolling through the

available datasets (subjects) in the Dataset
pane. You can also calculate a single subject
(or dataset), selected subjects or all subjects.
Population Access the population pharmacokinetic

analysis module to set-up initial parameter
estimates, run analysis, add covariables and
model validation.
Graph Access built-in graphical tools to create and

organize graphs.
Statistics Access a series of statistical tests for use in

bioequivalence.

Starting Kinetica
Option Description
Tools Access options for password protection,

Method Editor, Designers, Assistants,
Options (parameters) and Macros.
Help Access the online Help system, tutorials, and

license information.
Insert Commands You can insert several raw data text and/or numeric fields in a
Kinetica spreadsheet. All study and dataset text and numeric
fields are alphanumeric. You can define a text or numeric field by
entering text, numbers, or a combination of both. The new field
name is visible in the selected worksheet in the Dataset pane. You
do not need to work in a specific view when you insert a field.
Text fields will appear before numeric fields in the dataset and
global variables worksheets.
Insert commands are accessed from the Kinetica main menu. The
commands are described in the following table.
Option Description
Dataset Inserts a new dataset.
Worksheet Inserts a new worksheet for each defined

dataset.
Column Inserts a new column for all datasets in a

selected worksheet; text and numeric entries
are accepted.
Numeric Field Global – Inserts a numeric cell in the Global

Variables worksheet
Dataset – Inserts a numeric cell for each

dataset defined in the Dataset Variables
worksheet.

Starting Kinetica
Option Description
Text Field Global – Inserts a text cell in the Global

Variables worksheet.
Dataset – Inserts a text cell for each dataset

defined in the Dataset Variables worksheet.
Method Inserts a method in the Methods pane.
Pop Method Inserts a Population PK/PD method in the

Methods pane.
Inserting a New Dataset To insert a new dataset:
1. Select Dataset from the Insert menu. The Insert a Dataset

dialog appears.
Figure 2-2. Insert a Dataset Dialog
2. Enter an identifier for the new dataset in the Dataset Name

field.
Note The dataset name must be unique or it will not be

inserted. ▲
3. Click OK to insert the dataset and exit the dialog or click

Insert if you would like to add another dataset.
A new dataset is created with the same number of columns,

names of columns and methods as those existing in the pane
unless it is the first in an empty dataset. The new dataset is

Starting Kinetica
visible in the Plasma worksheet of the Dataset pane and the

All Variables worksheet of the Study pane.
Inserting a Column into a To insert a column into a worksheet:

Worksheet
1. Select Column from the Insert menu. The Insert a Column
dialog appears.
Figure 2-3. Insert a Column Dialog
2. Select the appropriate worksheet name from the Worksheet

List. The Worksheet List loads all worksheets found in the
Dataset pane.
3. Enter the name of the column you want to insert in the

Column Name field.
4. Click OK to insert the column and exit the dialog or click

Insert if you will add another column.
5. To add another column, repeat Steps 2-4. The column is

inserted to the right of the last column in the worksheet.

Starting Kinetica
Inserting a Dataset Numeric To insert a Dataset Numeric Field:

Field
1. Select Dataset Numeric Field from the Insert menu. The
Insert a Dataset Numeric Field dialog appears.
Figure 2-4. Insert a Dataset Numeric Field dialog
2. Type in an identifier for the new dataset numeric field in the

Field Name field.
3. Click OK to exit the dialog or click Insert if you will add

another numeric field.
4. To add another numeric field, repeat Steps 2-3. The new field
is added after the last field present in the All Variables view.
Inserting a Dataset Text Field To insert a Dataset Text Field:
1. Select Dataset Text Field from the Insert menu. The Insert a
Dataset Text Field dialog appears.
Figure 2-5. Insert a Dataset Text Field Dialog
2. Type in the name for the new dataset text field in the Field
Name field.

Starting Kinetica

another text field.
4. To add another text field, repeat Steps 2-3. The new field will
be added after the last field defined in the All Variables view.
Inserting a New Worksheet To insert a new Worksheet:
1. Select Worksheet from the Insert menu. The Insert a

Worksheet dialog appears.
Figure 2-6. Insert a Worksheet Dialog
2. Enter the name for the worksheet in the Worksheet Name

field.

another worksheet.
4. To add another worksheet, repeat Steps 2 and 3.

Starting Kinetica
Inserting a Global Numeric Field To insert a Global Numeric Field:
1. Select Global Numeric Field from the Insert menu. The

Insert a Study Numeric Field dialog appears.
Figure 2-7. Insert a Study Numeric Field Dialog
2. Type in the name of the new global numeric field. For

example, type in Weight.

another numeric field.
4. To add another numeric field, repeat Steps 2-3. The new field
will be added after the last field present in the Study Variables
view.
Inserting a Global Text Field To insert a Global Text Field:
1. Select Global Text Field from the Insert menu. The Insert a
Study Text Field dialog appears.
Figure 2-8. Insert a Study Text Field Dialog

Starting Kinetica
2. Type in the name of the new global text field in the Field
Name field.

additional text fields.
4. To add another text field, repeat Steps 2-3. The new field is
added after the last text field but before the first defined
numeric field.
Inserting a Method To insert a Method:
1. Launch Kinetica and use the Normal template.
2. Select Method from the Insert menu. The Method Selection

dialog appears.
Figure 2-9. Method Selection Dialog
3. Choose a hard-coded model method or a soft-coded method

from the available lists.

Starting Kinetica
4. Make the selections under the User names and Worksheets

columns corresponding to the Input Cols&Vars and Output
Cols columns, by clicking on the associated drop down lists.
5. Click Insert, and then click OK to exit the Method Selection

dialog.
Inserting a Population PK/PD To insert a population PK/PD method:

Method
1. Launch Kinetica and open the appropriate file.
2. Select Pop Method from the Insert menu. The Method

Selection dialog appears.
3. Select a population PK/PD method from the available list

(e.g. PopFitMicroIVBolus1comp) to activate Kinetica
Population.
4. Map the input columns (e.g. Time for X and Concentration

for Y) Make selections under the User names and Parameter

Starting Kinetica
columns corresponding to the Input Cols&Vars, Output Cols

and In/Out Vars columns, by clicking on the associated drop
down lists.
Parameters have a Yes or No option. If you select Yes, you are

prompting Kinetica to calculate the parameter. If you select
No, you are specifying that there is an existing value for the
parameter and thus the parameter will not be recalculated.
5. Click Datasets. The Select Dataset dialog appears.
Figure 2-11. Select Dataset Dialog
6. Use the Ctrl key and mouse to select a particular range of

datasets or click Select All to include all datasets.
7. Click OK to exit the Select Dataset dialog.
8. Click Insert, and then click OK to exit the Method Selection

dialog.
For more information, see the chapter, “Population

Pharmacokinetics.”

Starting Kinetica
Using the Delete Once you have mastered building your own data structures, you
Commands may need to delete some of the fields you created. Kinetica offers
most of the standard commands for editing the data structure.
These options are found in the Edit item in the main menu and
are described in the following table.
Option Description
Dataset Deletes the specified dataset.
Worksheet Deletes the specified sample for each

defined dataset.
Column Deletes the specified column for all

datasets in a selected sample.
Global Numeric Field Deletes the specified numeric cell for

each dataset found in the Global
Variables view.
Global Text Field Deletes the specified text cell for each
dataset found in the Global Variables
view.
Dataset Numeric Deletes the specified numeric cell for

Field each dataset found in the All Variables
and Study Variables views.
Dataset Text Field Deletes the specified text cell for each
dataset found in the All Variables and
Study Variables views.
All Dataset Info Deletes all dataset input.
Study Info Deletes all study information.
Rename Dataset Renames the specified dataset.
Remove Last Method Deletes the last method in the list of

methods along with all output
columns and variables associated with
the last method.

Starting Kinetica
Option Description
Remove All Methods Deletes all methods in the list of

methods along with all output
columns and variables associated with
the methods.
Remove Last Pop Deletes the last method in the list of

Method population methods. You can
manually remove study and dataset
output columns and variables, and any
information appearing in the Study
and Dataset views.
Remove All Pop Deletes all methods in the list of

Methods population methods. You can
manually remove study and dataset
output columns and variables, and any
information appearing in the Study
and Dataset views.

Starting Kinetica
Deleting a Dataset To delete a dataset:
1. From the Edit menu select Delete Study Object, and then
Dataset. The Delete a Dataset dialog appears.
Figure 2-12. Delete a Dataset Dialog
2. Select the dataset you want to remove from the available list.
3. Click Delete. The dataset is deleted from the Dataset pane.
4. Click OK to exit the dialog.
Once you delete a dataset, you notice that all data pertaining
to the deleted dataset has also disappeared from the Study
pane (Dataset Variables and Global Variables views).

Starting Kinetica
Deleting a Worksheet (Matrix) To delete a worksheet (matrix):
1. Select Delete Study Object, and then Dataset from the Edit
menu. The Delete a Study Worksheet dialog appears.
Figure 2-13. Delete a Study Worksheet Dialog
2. Select the name of the worksheet you want to remove from

the available list.
3. Click Delete. The worksheet is deleted from the Dataset

pane.

Starting Kinetica
Delete a Column To delete a column:
1. Select Delete Study Object, and then Column from the Edit
menu. The Delete a Column dialog appears.
Figure 2-14. Delete a Column Dialog
2. Select the name of the column you want to remove from the
available list.
Note If only one worksheet is defined, the column names

are displayed in the Columns List. If multiple worksheets are
defined, the column names are displayed in the Columns List
along with the worksheet name, for example PLASMA.X
where PLASMA is the worksheet and X is the column name.
▲
3. Click Delete. The column is deleted from the Dataset pane.

Starting Kinetica
Deleting a Global Numeric Field To delete a Global Numerical Field:
1. Select Delete Study Object, and then Global Numeric Field

from the Edit menu. The Delete a Study Numerical Field
dialog appears.
Figure 2-15. Delete a Study Numerical Field Dialog
2. Select the name of the study numeric field you want to

remove from the available list.
3. Click Delete. The study numeric field is deleted.

Starting Kinetica
Deleting a Global Text Field To delete a Global Text Field:
1. Select Delete Study Object, and then Global Text Field from
the Edit menu. The Delete a Study Text Field dialog appears.
Figure 2-16. Delete a Study Text Field Dialog
2. Select the name of the Study text field from the available list.
3. Click Delete. The study text field is deleted.

Starting Kinetica
Deleting a Dataset Numerical To delete a Dataset Numerical Field:

Field
1. Select Delete Study Object, and then Dataset Numeric Field
from the Edit menu. The Delete a Dataset Numerical Field
dialog appears.
Figure 2-17. Delete a Dataset Numerical Field Dialog
2. Select the name of the dataset numeric field from the

available list.
3. Click Delete. The dataset numeric field is deleted.
Deleting the Last Method To delete the last method:
1. Select Remove Last Method from the Edit menu. The

following prompt appears: “Are you sure you want to delete
the last method?”
Warning All data stored with the last method will also be
deleted. ▲

Starting Kinetica
2. Click Yes to delete the method. Click No if you do not want

to delete the method.
Deleting All Methods To delete all methods:
1. Select Remove All Methods from the Edit menu. The

following prompt appears: "Are you sure you want to delete
all methods?"
Warning All data stored with the methods will also be

deleted. If you open a template and select this option, all
Method columns will be deleted. ▲
2. Click Yes to delete the methods. Click No if you do not want

to delete the methods.
Deleting Any Method To delete any method:
1. From the Edit menu select Remove Any Methods. The

Delete Method (Step 1 of 2) dialog will appear.

Starting Kinetica
Figure 2-18. Delete Method (Step 1 of 2) dialog
2. Select the method to be removed and click Next.
3. In Step 2, choose the output columns and variables of the

selected method to be deleted. Click Finish to complete
removal of the method.

Starting Kinetica
Figure 2-19. Delete Method (Step 2 of 2) dialog
Deleting the Last Population When you delete a population method, you manually remove
Method study and dataset output columns and variables. You can also
remove any information appearing in the Study and Dataset
views.
1. Select Remove Last Pop Method from the Edit menu. The
the last pop method?”
2. Click No if you do not want to delete the method. Click Yes

to delete the method. The Select Columns and Variables to
Remove dialog is displayed.

Starting Kinetica
Figure 2-20. Select Columns and Variables to Remove

Dialog
3. Highlight the appropriate columns, dataset, and study

variables to remove by clicking on each item.
4. To remove information from the Study Info view, select the

Clear Study Info check box.
5. To remove information from the Dataset Info View, select

the Clear All Dataset Info check box.
6. Click OK to save your selections and exit the dialog.

Starting Kinetica
Deleting All Population Methods When you delete all population methods, you manually remove
study and dataset output columns and variables. You can also
remove any information appearing in the Study and Dataset
views.
1. Select Remove All Pop Methods from the Edit menu. The
all pop methods?”
2. Click No if you do not want to delete the population

methods. Click Yes to delete the population methods. The
Select Columns and Variables to Remove dialog appears.
3. Highlight the appropriate columns, dataset variables, and

study variables to remove by clicking on each item.
4. To remove information from the Study Info View, select the

Clear Study Info check box.
5. To remove information from the Dataset Info view, select the

Clear All Dataset Info check box.
Using the Extract Study Creating your own data structure is a good idea when you first
Command begin using Kinetica because it ensures you understand how the
program functions. However, to avoid undue process steps, a
feature in the application allows you to extract parts of a study to
create a new study.
Extracting fields from studies to create new data structures is

quite simple. Before you can extract any fields you must open an
existing dataset or template using the Extract Study dialog.

Starting Kinetica
Extract Study Dialog This dialog is accessed by selecting Extract Study from the Edit
menu. The contents of the dialog vary depending on the structure
of the dataset or template you open.
The dialog is divided into two sections: Datasets and Data. The
Datasets area, on the left side of the dialog, displays all datasets
found in the current structure. The Data area is split into two
components: Columns and Variables. The Columns component,
located in the middle of the dialog, displays all columns found in
the structure (remember, the identification convention for
columns is Worksheet.ColumnName i.e. Plasma.X). The
Variables component, on the right side of the dialog, displays all
study/dataset numeric/text fields found in the structure.
Extracting Fields from a Study To extract fields from a study:
1. In Kinetica, open the appropriate dataset or template.
2. From the Edit menu select Extract Study. The Extract Study
dialog appears.
Figure 2-21. Extract Study Dialog
3. Select the datasets you want to extract by clicking once on

each dataset identifier.

Starting Kinetica
4. Select the columns you want to extract by clicking once on

each column identifier. The worksheet containing the column
is created automatically.
5. Select the variables you want to extract by clicking once on

each variable identifier.
6. Click OK.
The new structure is created in the workspace. You can

continue to add/edit fields and save the structure as a dataset
or template.
Note The extracted structure appearing on your screen is

named Extract.kdb, by default. You can rename the structure
using the Save As dialog, accessed by selecting Save As from
the File menu. ▲

Starting Kinetica
Kinetica Toolbar The Kinetica toolbar provides an alternate method for accessing
various workspace and viewing options. The availability of the
items depends on whether you open a dataset or a template. The
various toolbar buttons are described in the following table.
Button Action
Compile macro
Insert or remove a macro break point (Stop toggle)
Evaluate the expression (Quick watch)
Step through macro code line by line
Step over macro lines
Run macro
Stop macro
Import PCNonlin
Import Phast
Import Siphar dos
Increase the spreadsheet magnification
Reduce the spreadsheet magnification
Restore the spreadsheet view to default dimensions
Left justify the contents of a cell

Starting Kinetica
Button Action
Center the contents of a cell
Right justify the contents of a cell
Bold the contents of a cell
Italicize the contents of a cell
Underline the contents of a cell
Invert columns and rows
Execute Table Assistant
Execute Import Assistant
Execute NCA Assistant
Execute Chart Wizard
Update or insert user license
Move to the previous or next screen
Open a new default data structure
Open an existing dataset
Save the current dataset
Cut the current selection to the clipboard

Starting Kinetica
Button Action
Copy the current selection to the clipboard
Paste the contents of the clipboard into selected

cells
Print the current selection of cells
Launch Report Setup
Export to Microsoft Word
Export to Microsoft Excel
Display the Kinetica About dialog box
Insert a method
Insert a population PK/PD method
Run a population method analysis without

covariables
Set initial parameter estimates for the EM

algorithm
Calculate the current dataset
Calculate a range of the dataset
Calculate all datasets
Plot the selected columns

Starting Kinetica
Button Action
Display all graphs
Move to the first dataset
Move to the previous dataset
Display dataset
Move to the next dataset
Move to the last dataset

Starting Kinetica
Kinetica Views The Kinetica views are located in panes on the left side of the
workspace.
Study Pane The Kinetica Study pane displays worksheets containing all global
information related to the study. Data shown in the study
spreadsheet views are not time-dependent in nature (for example,
Tmax, Cmax, etc). This enables you to quickly view information
across all subjects in the study.
The views available in this pane are listed in the following table.
Study Icon Study View Description
Dataset Variables Non time-dependent values unique to a dataset

computed during an analysis.
Global Variables Values that are global to a study, for example, study
name, study notes, population parameter mean and
variance.
Study Info Text area where computed information global to the

study is stored, e.g., statistics calculated from mean
curves.
Study Objects Displays the study structure, the objects in the

structure and the nature of those objects.
Macro Editor A VBA editor where input/output routines for

creating internal structures can be created, compiled,
and modified.
Spaghetti Plot By default, when a study is opened, this plot uses the
two left-most columns for all subjects, found in the
first sample matrix to create a graph.

Starting Kinetica
Study Icon Study View Description
Mean Curve Kinetica offers the generation of mean curves, with

two different menu options. The first option plots an
overlay graph with up to three separate mean curves.
The second option is a mean curve by group, with the
ability to choose any groups within the available
Kinetica structure.
Intelligent The intelligent spreadsheet allows user to paste

Spreadsheet dataset-column-type (similar to the WinNonlin
format) data and use the intelligent import under the
Tools menu to bring data to the Kinetica structure.
Dataset Pane The Kinetica Dataset pane displays views containing specific
information relating to the subjects in the study. Data shown in
the Dataset spreadsheet views are time-dependent (for example,
AUC, Cumulative AUC, etc.). The term dataset is used because
Kinetica allows multiple subjects to have the same identifier. This
is practical when dealing with bioequivalence. There are three
default views in the Dataset pane plus an additional view for each
sample you specify, for example, plasma, urine, etc.

Starting Kinetica
The views available in the Dataset pane are listed in the following
table.
Dataset Icon Dataset Description

View
Sample Time-dependent values that are

Matrix specific to the subject sample
matrix, e.g., Plasma.
Dataset Text area where information is

Info recorded or specific
transformations made when
analyzing the selected subject.
Dataset Displays a graphical plot of the

Graph first two left-most columns of the
sample view.

Starting Kinetica
Methods Pane The Kinetica Methods pane displays views containing

information corresponding to the methods inserted in the study.
The views available in this pane are listed in the following table.
Methods Icon Methods Description

View
Methods Displays the list of methods

inserted into the study and the
available options selected for
each.
LZ Launches an LZ Graph based

Graph on the AUC* Method inserted
Method A VBA editor enabling you to

Editor create and modify methods and
integrated or differential
models.
Tables Pane The Kinetica Tables pane displays the Table Assistant view.
Table Icon Table Description

View
Table Tables are listed as views within the

Info Kinetica Tables pane in order of
creation. A single click on a table
view will re-generate the table
inside Kinetica, using the most
recently computed data.

Starting Kinetica
Reports Pane The Reports pane displays the current report defined by selecting
Report Setup from the File menu.
Reports Icon Reports Description

View
Report Displays the list of methods

Info inserted into the study and the
available options selected for each.
My Displays the report created using

Report the Report Setup option.
Gallery Pane The Gallery pane displays all graphs generated during analysis, or
graphs sent to the Gallery.
Gallery Icon Gallery Description

View
Gallery Displays all computed and/or

selected study graphs. You can
view or modify single or all
available graphs.
Current Magnifies the current graph to full

Graph screen mode.

Starting Kinetica
Exchange Pane The Exchange pane displays a list of active web views enabling
you to share data with colleagues or to view research data on the
World Wide Web.
Exchange Icon Exchange Description

View
My Integrated set of web pages

Exchange including FDA news items,
the latest industry news and
internet links. You can
customize this page, as
required.
Thermo Thermo Fisher Scientific

Fisher home page with links to
Scientific services, training resources,
products and support.
Resources List of pharmacokinetic

resources. You can also
request links to be added to
this page.
Intranet Enables you to create your

own centralized intranet and
share objects such as PK/PD
reports with your colleagues.

Starting Kinetica
Kinetica Status Bar The Status Bar is found along the bottom edge of the workspace.
It is an information line noting the application status (Ready or
Done). It also displays the actual numerical value of an individual
cell when the cursor is placed in that cell, the window that is
currently active, and license information.

Starting Kinetica
Kinetica Spreadsheet When you launch Kinetica and open a template or dataset, the
spreadsheet interface appears. Whether you have data present or
Interface an empty template, any changes you make will only be applied to
the pane that is currently active. The spreadsheet view contains
the raw and computed column data used in the analysis.
Figure 2-22. Kinetica Spreadsheet Interface
The default view in both the Study and Dataset panes is

organized in columns. You can organize rows of data by clicking
the Invert Columns and Rows button on the main toolbar. You
can also zoom in/out or select the full-page view option from the
menu bar or main toolbar.
Note Units of measurement are always stored in the first row of

a Kinetica spreadsheet, labeled Unit (see figure above). ▲
Formatting Kinetica Kinetica offers numerous formatting options for dataset

Spreadsheets spreadsheets. You can format the cells in a spreadsheet, format
adjust individual columns and rows, or adjust all columns and
rows in a spreadsheet.
In Kinetica, numerical values are displayed and printed in f

format. The f format takes the form [-]dddd.dddd, where dddd is
one or more decimal digits. The number of digits before the
decimal point depends on the magnitude of the number, and the
number of digits after the decimal point depends on the number
of decimal places specified. Trailing zeros are truncated, and the
decimal point appears only if one or more digits follow it.

Starting Kinetica
Note If, for example, a value is 34.565457. In Kinetica, it will

be displayed as 34.5655, by default. You can change the display
by specifying the required number of decimal places in the
Format tab of the Cells dialog. ▲
Formatting Cells You can format cells using the Cells dialog, which provides
numerous options for formatting spreadsheet cells.
Cells Dialog
This dialog is accessed by selecting Cells from the Format menu.

There are five formatting options available: Format, Font, Color,
Borders and Align. The options are included on separate tabs
described in the following table.
Tab Description
Format Specify the number of decimal places for data. You

can specify a maximum of 6 decimal places.
Font Specify font effects such as bold, italic, color,

underlining, outlining, etc.
Color Color the foreground and background of dataset

cells, shade cells with a pattern or give cells
dimension.
Borders Add a specific type of border and/or border color to

cells.
Align Adjust data horizontally and vertically within cells.

You can also select the Wrap Text, Auto Size and
Allow Enter options by selecting the appropriate
check boxes.
Note Changes are applied only to the cells you select in the
spreadsheet. ▲

Starting Kinetica
Formatting Cells in a Spreadsheet
To format cells in a spreadsheet:
1. Select Cells from the Format menu. The Cells dialog appears.
Figure 2-23. Cells Dialog
2. Specify or modify font, font effects, color, border properties,

etc., as required.

Starting Kinetica
Adjusting Individual Columns All Kinetica spreadsheet columns are set to a standard width.
and Rows in a Spreadsheet Although row height is set to a default, it automatically adjusts to
accommodate the largest font entered into the row. Column
width does not adjust unless you modify it. You have the option
to change the standard column width and row heights for
individual worksheets in a group.
A Manually drag the sides of a cell up and/or down with your

mouse to adjust the standard column width and row heights for
individual worksheets in a group. The information is stored and
the adjusted size is used until you close the file.
Adjust All Columns and Rows in To adjust all columns in a spreadsheet:

a Spreadsheet
1. Click the top left cell of the worksheet.
2. Drag the border below any selected row heading until the row
is the appropriate height.
3. Release the mouse button. All the selected rows are resized.

Starting Kinetica
Move Columns You can Move or Sort columns by selecting Edit>Move

Columns:
Figure 2-24. Move/Sort Columns Example — Selecting Move Columns from the Edit menu
A dialog box appears. Select the column to move and use the up
or down arrow to move the specific column. User can
use the icon to order the column in alphabetical order.

Starting Kinetica
Figure 2-25. Move/Sort Columns Example — Choosing which columns to move/sort
Note You can only Sort columns if they are the same type
(Numeric or Text). ▲

Starting Kinetica
Changing the Dataset In Kinetica you may transpose columns or rows to change how
View your data are displayed. This option is accessible from the main
menu by selecting Invert columns and rows from the View menu,
or by clicking the Invert columns and rows button (illustrated
below). This button is available to invert columns and rows in
both the Study and Dataset levels.
Figure 2-26. Invert Columns and Rows Button
Protecting Kinetica Kinetica gives you the ability to protect datasets using password
Datasets protection. You can lock a dataset completely or make the data
read-only. To apply a password:
1. Select Protection then Password or Read Only Password from

the Tools menu. The Open Password dialog appears.
2. Enter your password and click OK.

Starting Kinetica
Removing Password Kinetica allows you to remove previously set open and read-only
Protection passwords. To remove password protection:
1. Select Embedded Objects then select either Remove Read-

Only Password or Remove Open Password from the Tools
menu. When a read-only password or an open password is
present, this option will be enabled.
Figure 2-27. Read Only Password dialog
2. Enter the current password in the dialog box and click OK.
Protecting Kinetica Kinetica provides the ability to protect macros using password
Macros and Removing protection. A user may lock a macro and make the macro script
accessible only by password. To protect a macro script:
Password Protection
1. Select Macro then Macro from the Tools Menu. The macro
dialog appears.
2. Select a macro from the list (if macros were previously created
in the file), and then click the Password button. The Set
Macro Password dialog appears.

Starting Kinetica
Figure 2-28. Set Macro Password dialog
3. Enter your password in both the New Password and Confirm

Password fields, and click OK.
Removing Macro Password To remove macro password protection:

Protection
1. Select Macro, and then Macro from the Tools Menu. The
macro dialog appears.
2. Select a macro with existing password protection, then click

the Remove Password button (The Remove Password button
will be enabled if password protection was previously set).
The Open Password dialog appears.
Figure 2-29. Open Password dialog
3. Enter the password and click OK. A message box confirming

removal of the password appears. Click OK again.

Starting Kinetica
Kinetica Default Data Kinetica uses a dynamic data structure enabling you to create and
edit almost any organization.
Structure
The default data structure contains default panes and views that
cannot be deleted or omitted from the structure.
When you select New from the File menu, you are opening the
default data structure “Plasma.” You can then add fields to this
basic structure. Although you are given the flexibility to add
whatever fields required, it is much quicker to open, edit and
resave the structure of one of the existing templates or datasets
included with Kinetica. However, when you are new to Kinetica,
it is a good idea to try one of your own in order to fully
understand the data structure.
After you open the default data structure you can start building
your own fields. These fields are empty and prepared for raw data
entry. It is important to note that Kinetica does not automatically
fill in the fields you create after an analysis. The only fields
Kinetica fills in after an analysis are those created when you add a
method, or if you open a template with existing methods.

Starting Kinetica
Notes

3. Opening and Saving Data
Files
This chapter provides information on opening and saving data
files within Kinetica.

Opening and Saving Data Files
Files in Kinetica Kinetica files have a kdb (Kinetica DataBase) extension. Kinetica
templates are files with a ktp (Kinetica TemPlate) extension.
The Kinetica kdb file format holds Kinetica data and datasets,
including methods, settings, table scripts, and appended macros.
The Kinetica ktp file format is a template file that contains
methodologies, pre-defined settings for the methods, table scripts,
macros and appended graphs.
When you open a ktp file, it is automatically renamed with a kdb

file extension and is formatted for use with data entry or import.
Both the kdb and ktp file types are private formats; neither
format can be edited outside of Kinetica.
Note Kinetica 5.0 is not backward-compatible. Files created or

saved using Kinetica 5.0 will not be able to be opened with
previous versions of Kinetica. ▲

Opening an Existing To open an existing Kinetica file:

Kinetica File
1. Within Kinetica, select Open from the File menu. The Open
a Kinetica File dialog appears. By default the program
displays the sub-directories of the Data directory (see the
figure below).
Figure 3-1. Open a Kinetica File Dialog
2. Double-click on the directory corresponding to the type of

analysis you want to run, e.g. Convolution_Deconvolution.
The available datasets of the selected directory are displayed.
3. Double-click on the appropriate dataset (e.g.

Deconvolution.kdb) or right-click it with the mouse and
select Open. The selected file displays in the Kinetica
workspace.
Note You can open any valid Kinetica file by dragging and
dropping it onto the Kinetica workspace. You can also drag any
valid file onto the Kinetica icon. Kinetica will launch and open
the file. ▲

Customizing the Kinetica uses technology similar to Microsoft’s Word and Excel
programs, allowing you to create default file structures based on a
Normal Kinetica “normal” template. When you create a new file, Kinetica uses a
Template default structure called Normal.kdb that is stored in Kinetica’s
Data directory. By default, Normal.kdb contains the most basic
structure: one dataset containing an X-column and a Y-column
inside a plasma matrix. To customize Kinetica’s Normal
template, follow the steps below.
Note Make sure that you do not overwrite Normal.kdb. ▲
1. In Kinetica select New from the File menu. The New

Analysis dialog appears.
Figure 3-2. New Analysis Dialog
2. Select the Normal button located on the General tab.
3. Click OK. The Plasma dataset group appears:

Figure 3-3. Dataset View

dialog appears.
5. Enter Test in the Column Name field, and then click OK.
A column called Test appears in the Plasma view adjacent to

the Y-column. You may continue to add as many columns as
you like to Normal.kdb.
6. When you are finished adding columns select Save As from

the File menu to save your modified template as a new
template.

Opening an Existing To open an existing Kinetica template:

Kinetica Template
Analysis dialog appears. By default the program displays all
the subdirectories of the Template directory.
2. Select the tab corresponding to the type of analysis you want

to run, e.g. Non Compartmental. The available templates of
the selected directory are displayed:
Figure 3-4. New Analysis dialog open to Non

Compartmental tab, Extravascular template selected.
3. Click on the template you want to open, e.g. Extravascular

(see figure above).
4. Do one of the following:
• To open the selected template with example data, select

the Open with Data check box. If you do not check this
box, an empty template opens, ready for your own data.
• To view step-by-step help instructions related to the

selected template, check the Open with Help box.

5. Click OK. The selected template is displayed in the Dataset

pane.

Saving Kinetica Files When you save a Kinetica file you have three options:
• Save the file containing the raw data, analyzed data, graphs,
table scripts with all information.
• Save the file with all information under a different name.
• Save the file as an empty template.
These options are discussed in detail below.
Saving a Kinetica File To save a Kinetica file with its original file name:
Using Its Original File
Name 1. Launch Kinetica.
2. Open a valid dataset or template, enter data and/or compute

values, as required.
3. Select Save from the File menu or click the Save button on
the toolbar. The file is saved under its original name.
Saving a Kinetica File To save a Kinetica file with a new name:

with a New Name
1. Launch Kinetica.
2. Open a valid dataset or template, enter data and/or compute

values, as required.
3. Select Save As from the File menu. The Save As dialog

appears. By default the program displays the sub-directories of
the Data directory.

Figure 3-5. Save As Dialog
Note Make sure that you do not overwrite Normal.kdb. ▲
4. Select the appropriate directory where you want to save the

new file, e.g. Absorption. The existing datasets of the selected
directory are displayed.
5. Enter the new name for the file, e.g. myfile.kdb, and then
click Save. The selected dataset is saved under the new name.
The previous version of the file is saved under the original
name.
Saving a File as an Empty When you open or create a dataset (or another template), you can
Kinetica Template enter data and add methods. When the analysis is complete, you
will have a collection of fields and methods full of data. You can
save all your data in a .kdb file or you can save the file as a
template. Saving the file as a template preserves only the file
structure with the embedded methods; all data in the file are
deleted.
1. In Kinetica open a valid dataset or template, enter data and/or

compute values, as needed.

2. Select Save As Template from the File menu. The Save As

Template dialog appears.
Figure 3-6. Save As Template Dialog
3. Navigate through the Kinetica directories until you find the

directory where you want to save the new template.
4. Enter the new name for the template file, e.g., template.ktp
and then click Save.
Note By default Kinetica generates a default filename for

your template composed of the name of the current dataset
and a .ktp suffix. ▲

4. Unit Configuration in
Kinetica
This chapter provides information on configuring units of
measurement within Kinetica.

Unit Configuration in Kinetica
Configuring Units This section is specifically for Kinetica templates that do not have
a built-in unit management tool. These templates, such as those
for performing compartmental analyses, have units specified by
unit-handling methods. You may, however, want to create your
own methods/templates to understand how to set up your own
units.
You can specify the following types of units:
• Concentration
• Column
• Rate
• Molar
Note Non-compartmental analysis methods such as AUC*,

AUC steady-state*, AUC inter*, AUC steady-state with Lz*, and
sparse AUC* already have unit management that can be pre-
defined. ▲

Specifying Units Kinetica does not provide units for output variables, however, it
does provide the units for output columns. You must insert the
basic units for time, quantity (or amount), and volume. Do this
by inserting dataset and study numeric or text fields with the
relevant names typed on the fields provided.
Three hard-coded methods allow you to specify units:
• Column Unit
• Get Column Unit
• Set Column Unit
Three soft-coded methods allow you to specify units:
• MakeConcUnit
• MakeRateUnit
• Xyunit

Specifying You cannot enter concentration units; however, you can generate
the unit using the units for the amount and the volume (for
Concentration Units example, mg for the amount (dose) and µg/L for the
concentration). This is performed by inserting the soft-coded
method “MakeConcUnit.”
Inserting and Using the To insert and use the MakeConcUnit method:
MakeConcUnit Method
1. Select New from the Kinetica File menu. The New Analysis
dialog appears:
Figure 4-1. New Analysis dialog
2. Click on the General tab, select the Normal icon, and then
click OK.
3. Select the Global Variables worksheet in the Study pane. You

are now ready to insert text fields that can hold units of
measurement definitions.

Inserting Text Fields To insert text fields:
1. From the Insert menu select Global Text Field. The Insert a
Global Text Field dialog appears.
2. For this example, enter the text QteUnit,VolumeUnit in the

Field Name field.
Note The comma in the text string tells Kinetica that we

are creating two separate fields. ▲
3. Click Insert.
4. The global variables you’ve added now appear as the column

headings QteUnit and Volume Unit in the Global Variables
view of the Study pane.
Setting Units for Text Fields To assign units to the text fields you’ve inserted:
1. Enter the value mg (for milligrams) in the Unit row under the
QteUnit field and press the return key.
2. Enter the value L (for liters) in the VolumeUnit field and

press the return key.
3. From the Insert menu select Method (or use the Insert
Method button on the toolbar).
4. In the Method Selection pop-up window scroll down the list

of methods to the Soft Coded Methods.
5. Expand the list of soft-coded methods. Expand General and

select MakeConcUnit.bas.

Figure 4-2. Method Selection dialog – MakeConcUnit.bas selected for insertion
6. Before you can insert the method you must apply User names
to the Input Cols&Vars fields found at the top right of the
Method Selection dialog (see figure above).
7. Click inside the white area below User names to activate the
drop-down lists populated with your study variables. Select
Study.QteUnit for QteUnit and Study.VolumeUnit for
Volume Unit (refer to figure below).
Figure 4-3. Detail of Method Selection dialog: assigning

Input Cols&Vars for the MakeConcUnit method.
8. Click Insert to insert the method. When the method is

inserted click OK to exit the Method Selection dialog.
9. Select the Dataset Variables view in the Study pane to see the
new field, ConcUnit, added by the MakeConcUnit method.

10. Click the Calculate All button (or use the Dataset menu
and select Calculate All) to execute the method. The method
reads the unit definitions from the columns selected in Input
Cols&Vars and uses them to generate the unit for ConcUnit;
the value mg/L is inserted in the ConcUnit field.
Figure 4-4. Unit mg/L as generated by MakeConcUnit

method

Specifying Column Column units are entered by using the “Set Column Unit” hard-
coded method. Kinetica computes values using the time unit
Units specified and places the value in the appropriate column. This
method must be inserted into each column in which you need to
specify units.
If a template is open, the Set Column Unit method may already

be included. You can verify this by clicking Methods in the
Methods pane and viewing the list of methods in the spreadsheet.
Inserting and Using the To insert and use the Set Column Unit method:
Set Column Unit Method
Analysis dialog appears.
click OK.
3. Select the Global Variables worksheet in the Study pane. You

are now ready to insert text fields. (Refer to the Inserting Text
Fields section.)
Viewing the Inserted Units To view the inserted units:
1. Highlight the Plasma worksheet in the Dataset pane and click

the Calculate One button. The units are visible in the
spreadsheet.
2. Click the Insert Method button. The Method Selection

dialog appears.
3. Select the Set Column Unit method from the hard-coded

Methods list.
4. Select Plasma.Y from the Col User names drop down list in
the upper right area of the dialog (under User names).

5. Select ConcUnit from the Unit User names drop down list in
6. Click Insert. The method is inserted. This time Kinetica uses

the result of the MakeConcUnit method for the Y column
units.
Note You must have already inserted the MakeConcUnit

method in order to see the ConcUnit field in the list box. ▲
7. Click the Calculate All button. Kinetica inserts the value h in

the first row of the X column and mg/L in the first row of the
Y column.
8. Repeat this procedure to configure units for as many columns

as required.
Note The first row of sample worksheets is always reserved

for column units. ▲

Specifying Rate Units Rate units can be inserted using the "MakeRateUnit" soft-coded
method. Kinetica then computes values using the quantity (or
amount) and time unit specified and places the value in the
selected column. This method must be inserted for column(s)
where you want to specify the rate units.
If a template or dataset is open, the MakeRateUnit method may

already be included. You can verify this by clicking Methods in
the Methods pane and viewing the list of methods in the
spreadsheet.
Inserting and Using the To insert and use the MakeRateUnit method:
MakeRateUnit Method
1. Launch Kinetica.
2. Select New from the File menu or click the New button. The
New Analysis dialog appears.
click OK.
4. Highlight the Global Variables worksheet in the Study pane.

You are now ready to insert text fields.
Inserting Text Fields To insert text fields:
1. Select Global Text Field from the Insert menu. The Insert a
Global Text Field dialog appears.
2. Enter the text QteUnit,VolumeUnit,TimeUnit in the Field

Name field and click Insert.
4. Select Global Variables in the Study pane to view the inserted

global text fields.

5. Enter the value mg (for milligrams) in the QteUnit field and

6. Enter the value L (for liters) in the VolumeUnit field and

7. Enter the value h (for hours) in the TimeUnit field and press
the return key.
8. Select the Method pane and click on Basic Editor. The Basic
Editor dialog appears.
9. Click Open from the File menu. The Open dialog appears.
10. Select the soft-coded method called MakeRateUnit.bas from

the Kinetica\models\general directory.
11. Click Open. The following basic code appears in the Basic
Editor dialog:
Dim AmountUnit as InputText

Dim TimeUnit as InputText
Dim RateUnit as OutputText
Sub MakeRateUnit()
RateUnit = AmountUnit + "/" + TimeUnit
End Sub
12. Click the Insert Method button. The Method complies and
the following message appears: “Method successfully
compiled.”
13. Click OK. The Method Selection dialog appears. The

MakeConcUnit soft-coded method is included in the list of
soft-coded methods.

Note If the method does not compile properly, a message

appears informing you of the error and indicates the line of
code in which the error occurred. ▲
14. Select this method from the Methods list.
15. Select Study.QteUnit from the AmountUnit User names

drop down list in the upper right area of the dialog (under
User names).
16. Select Study.TimeUnit from the TimeUnit User names drop

down list in the upper right area of the dialog (under User
names). Click Insert. The method is inserted.
Viewing the RateUnit Output To view the RateUnit output field:

Field
1. Highlight the All Variables worksheet in the Study pane.
2. Click the Calculate All button. Kinetica inserts the value

mg/h in the RateUnit field (in blue).

Getting Units Sometimes you may want to get the units inserted from one
column for use in a new column. You can do this using the “Get
Column Unit” hard-coded method. Kinetica takes a copy of a
selected column unit that has already been specified and applies it
to another column.
If a template is open, the Get Column Unit method may already

be included. You can verify this by clicking Methods in the
Methods pane and viewing the list of methods in the spreadsheet.
Inserting and Using the To insert and use the Get Column Unit method:
Get Column Unit method
1. Complete the steps included in the procedure for calculating
observed concentration units (see the section Specifying
Concentration Units). ConcUnit is computed in the example
using the Get Column Unit method.

dialog appears.
3. Enter the text MyTest in the Column Name field.
4. Click Insert. You can view the new column “MyTest” in the
Dataset pane.

dialog appears.
6. Select the Set Column Unit method from the hard-coded

Methods list.
Note Since it is a hard-coded method, you cannot see the

Basic source code. ▲
7. Select Plasma.MyTest from the Col User names drop down

list in the upper right area of the dialog.

8. Click Insert. The method is inserted.

dialog appears.
10. Select the Set Column Unit method from the Methods list.
11. Select Plasma.MyTest (assuming we are using a Plasma

worksheet) from the Col User names drop down list in the
upper right area of the dialog (under User names).
12. Select ConcUnit from the Unit User names drop down list in
14. Highlight the Plasma worksheet in the Dataset pane.
15. Click Calculate One.
Viewing the Units Kinetica inserts the value mg/L in the first row of the MyTest
Inserted column. This unit is derived from whatever value is inserted and
output to the ConcUnit field.
The first row of the Plasma worksheet appears as follows:
X Y MyTest
h mg/L mg/L
Repeat the above procedure for as many columns as required.

Multiplying Units In the case where the values of one column are multiplied by
another column, Kinetica supplies the soft-coded method “XY
Unit” to insert the correct unit labels. The method creates a unit
label using the units specified from any two different columns or
fields.
If a template is open, the XY Unit Method may already be

included. You can verify this by clicking Methods in the Methods
pane and viewing the list of methods in the spreadsheet.
Inserting and Using the To insert and use the XY Unit Method we will multiply the
XY Unit Method ConcUnit by the RateUnit using the XY Unit method:

observed concentration units (see the section Specifying
Concentration Units).

rate units (see the section, Specifying Rate Units).

dialog appears.
4. Enter the text UnitTest in the Column Name field.
5. Click Insert, and then click OK to exit the dialog. You can
view the new column “UnitTest” in the Dataset pane.
6. Select the Method pane and click on Basic Editor. The Basic
Editor dialog appears.
7. Click Open from the File menu. The Open dialog appears.
8. Select the soft-coded method called XYunit.bas from the

Kinetica\models\general sub-directory.

9. Click Open. The following Basic source code appears in the

Method Editor dialog:
'XY unit
Dim XYunit as OutputText

Dim xunit as InputText
Dim yunit as InputText
Sub calc_XYunit()
XYunit = "(" + yunit + ")" + "." + "(" + xunit + ")"

End Sub
10. Click OK.
11. Click the Insert Method button. The method compiles and
the following message appears: "Method successfully
compiled."
12. Click OK. The Method Selection dialog appears. The XYunit
method is included in the list of soft-coded methods.
Note If the method does not compile properly, a message

appears informing you of the error and indicates in which line
of code the error occurred. ▲
13. Select this method from the soft-coded Methods list.
14. Select ConcUnit from the xunit User names drop down list in
15. Select RateUnit from the yunit User names drop down list in
17. Highlight the All Variables worksheet in the Study pane.

18. Click the Calculate All button. The value (mg/h) (mg/L) is
inserted in the XYunit field.
To view the XYunit output Now we will assign this XYunit label to the UnitTest column we
field inserted using the Set Column Unit method.

dialog appears.
2. Select the Set Column Unit method from the Methods list.
3. Select Plasma.UnitTest from the Col User names drop down

list in the upper right area of the dialog.
4. Select XY Unit from the Unit User names drop down list in
the upper right area of the dialog.
Viewing the Inserted To view the inserted units:

Units
1. Highlight the Plasma worksheet in the Dataset pane.
2. Click the Calculate One button. The value (mg/h).(mg/L) is

inserted in the first row of the UnitTest column. This unit is
taken from whatever value is inserted and output to the
XYunit field. The first row of the Plasma worksheet appears
as follows:
X Y UnitTest
h mg/L (mg/h).(mg/L)
3. Repeat this procedure for as many columns as required.

Obtaining Simplified Generally, units are inserted by the method used in the output
Units columns. However, Kinetica does not simplify the units when
possible. In some templates you can find methods that direct the
program to put simplified units in a particular column. For
example, in the Deconvolution.ktp template there are two
columns that do not have units in the output columns:
dA
• – the rate of change of the amount of drug absorbed with
dt
time.
• A(t) – the amount of absorbed drug.
To see an example of a template containing units handling

methodologies, open Deconvolution.ktp (with data) which
provides dA/dt and A(t). You can also refer to the following three
methods:
• MakeRateUnit – inserts the unit for the rate by associating

the Study.AmountUnit field with the Study.TimeUnit field.
• Set Column Unit – inserts the unit for the rate by associating
the os.dA/dt column with the RateUnit field (assuming we
are using an os worksheet.)
• Set Column Unit – inserts the unit for the rate by associating
the os.A(t) column with the Study.AmountUnit field.
Unit Management for AUC You can use the Unit Management feature to specify the input
Methods units for the AUC methods. AUC methods include:
• AUC*
• AUCinter*
• AUC Steady State*
• AUC Steady State with Lz*
• Sparse AUC

Chapter 8, Non-Compartmental Analysis discusses the AUC

methods in detail.
To use the Unit Management feature, you need to specify the

input units and select the type of units for the output variables.
Unit Management will then convert the units to your
specifications. We provide an example of this procedure below.
1. In Kinetica select the Methods pane.
2. Using Insert > Method… from the Menu bar or the Insert
Method button on the toolbar, select and insert one of the
AUC methods. After inserting the method the Methods view
will appear as follows:
Figure 4-5. Methods view after insertion of the AUC Steady State* method
3. Click Set under Global Options. The AUC* Method Global

Options dialog appears.

Figure 4-7. AUC Method Global Options Dialog – Units Tab
4. Select the Units tab.
5. Under the Selected Unit column, specify Time,

Concentration, and Dose units from the drop down list
according to your input data. You can change the display of
the units using the Display Label column (see figure above).
6. Select the units for the output variables.
7. Click OK.

Specifying Molar You can use the Unit Management feature to specify molar units
for the AUC* method. You can define a different molecular
Units for the AUC* weight for each dataset in a selected study, or, if you select the
Method global option, all datasets in the study.
To use this feature, you must specify:
• Input units for quantity (such as dose) and concentration
• Molecular weight
• Type of units for the output variables.
The units are then converted according to your specifications.
Note Ensure that you define molar units for each AUC*
method. Each AUC* method is related to a particular defined
molecular weight. ▲
Specifying Molar Units Use the 2WayCrossover.kdb for this exercise. To specify molar
units:
1. In Kinetica select the Methods pane.
2. Select the AUC* method.
• Click Set under Global Options (defines the molecular

weight for all datasets in the study).
• Click Set under Local Options (defines the molecular

weight for an individual dataset in the study). The AUC*
Options dialog appears.

Figure 4-8. AUC* Method Global Options Dialog – Units Tab
5. Under the Selected Unit column, specify Time (e.g. h),

Concentration (e.g. mg/mL), a Dose (e.g. mg), AUC (e.g.
M*h) and any other required units from the drop down list
the units under the Display label column.
• Select Variable Name and select the appropriate variable

name for the molecular weight from the available list.
Select this option if the variable already exists in the

dataset numerical field (All Variables view in the Study

pane).
• Select Value and enter a numerical value for the

molecular weight in the adjacent field.
8. Click Apply and/or click OK to save the selections and exit

the dialog.
Viewing the Inserted Units To view the inserted units:
1. Highlight the Plasma worksheet in the Dataset pane

(assuming we are using a Plasma worksheet).
2. Click the Calculate One button.
The first row of the Plasma worksheet appears as follows:
X Y AUC
h mMolar mM.h

Notes

5. Importing and Exporting
Data
The following chapter describes the different ways to import and
export data in Kinetica.

Importing and Exporting Data
Intelligent Kinetica provides a rapid and easy-to-use method to import data

from Excel or WinNonlin into Kinetica. Note that the data in the
Spreadsheet and Intelligent Spreadsheet is not saved when the file is closed; use it
Intelligent Import for quick import into the Kinetica structure. Intelligent Import
recognizes two types of data layout: Dataset Column and XYj.
These are described below.
Dataset Column The Dataset Column layout option indicates that the selected
range of Excel data is stored in column format with Time and
Concentration columns. These columns are stacked ‘vertically’
per dataset, and the subject ID repeats. See the table below for an
example:
Subj Time Conc
Subj101 x y
Subj101 x y
Subj101 x y
Subj101 x y
Subj101 x y
Subj102 x y
Subj102 x y
Subj102 x y
Subj102 x y
Subj102 x y

Example In this example we use Intelligent Import to transfer data from an

Excel worksheet into Kinetica’s Intelligent Spreadsheet in the
Dataset Column layout. We use the file DatasetColumn
Import.xls found in the Kinetica/Data folder.
1. In Kinetica, select Intelligent Spreadsheet in the Study pane.
2. With DatasetColumn Import.xls open in Excel, copy the

spreadsheet content and then go to Kinetica and paste it into
the Intelligent Spreadsheet. The column headings should
appear in the first row (see figure below).
Figure 5-1. Intelligent Spreadsheet after pasting in data copied from Excel
3. Select Intelligent Import from the Tools menu. The

Intelligent Import pop-up window appears:

Figure 5-2. Intelligent Import window
The table below describes the different fields in the Intelligent

Import window.
Selection Description
Variables Strings from the first row of cells of the Intelligent Spreadsheet, as read by
Intelligent Import.
Sort Variables Entries or selections in this box are used to identify the Dataset name of the
(Dataset Name) Kinetica file. Entries in this box will also be populated as dataset fields in the
Dataset Variables level of the Kinetica data structure.
Carry Alongs Entries in this box will be populated as dataset fields in the Dataset Variables
level of the Kinetica data structure. The data in this box should be unique to
the dataset name such that there is only one value for each individual dataset
name.
Time Series Data Entries in this box will be populated as new columns in the first available
worksheet. The columns handle both numeric and text entries. For example,
comments related to a specific time-concentration data can be brought into
the Kinetica data structure.
Units in Second If your spreadsheet has units in the second row, check the Units in Second
Row box Row box. Intelligent Import will bring the second row to the unit rows.

XYj Data Type Indicates that data are stored in column format with one Time column at the
box first column that is the same for each subject but with different Concentration
columns.
4. Intelligent Import reads the first row of the Intelligent

Spreadsheet and adds the cell values to the Variables list.
5. Drag and drop variable names from the Variables list to the
other text boxes of the Intelligent Import window as follows:
• DrugName and SbjName to Sort Variables (Dataset

Name)
• Dose and Sequence to Carry Alongs
• SampleTime, SampleValue, and SampleStatus to Time

Series Data
6. When you are done, the Intelligent Import window will look
similar to the figure below:
Figure 5-3. Intelligent Import after organizing variables into categories.

Note If your spreadsheet has units in its second row, check

the box Units in Second Row. ▲
7. Click Import. Kinetica displays a message when the import is

complete. Once the data are imported, you can associate
methods to compute pharmacokinetic parameters (see
Chapter 8, “Non-Compartmental Analysis”).
XYj The XYj layout option indicates that the selected range of Excel
data is stored in column format with one time column as the first
column that is the same for each subject but with different
Concentration columns. Note that there could be more than one
concentration column associated with a subject. These columns
are arranged ‘horizontally’ per dataset. See the example below:
Time Subj101 Subj102 Subj103
x y Y y
x y Y y
x y Y y
x y Y y
x y Y y
Example In this example we use Intelligent Import to transfer data from an

Excel worksheet into Kinetica’s Intelligent Spreadsheet in the XYj
layout. We use the file XnY Import.xls found in the
Kinetica/Data folder.
1. In Kinetica, select Intelligent Spreadsheet in the Study pane.
2. With XnY Import.xls open in Excel, copy the spreadsheet

content, then go to Kinetica and paste the data into the
Intelligent Spreadsheet. The column headings should appear
in the first row.

3. Select Intelligent Import from the Tools menu. The

Intelligent Import pop-up window appears; the first row of
the Intelligent Spreadsheet is shown as list of variables.
4. Check the box XYj Data Type. Notice that when the box is
checked, the values in the Variables section of the Intelligent
Import window disappear. Intelligent Import assumes that
the first column is the time column and that the remaining
columns are individual dataset data. The first row starting
from the second column is used as the dataset name for the
Kinetica study.
5. Click Import. Kinetica displays a message when the import is

complete.

Importing Files into Kinetica includes an easy-to-use utility called Import Assistant.
With Import Assistant you can import Microsoft Excel, ASCII,
Kinetica with Import Watson LIMS data, and the proprietary formats of P-Pharm and
Assistant Siphar data.
The Import Assistant allows you to append new data to existing

study data, insert data into empty study templates, or create a
new study structure.

Using the Import The Import Assistant Wizard is a series of dialogs that simplifies
importing data and guides you through the process step-by-step.
Assistant Wizard The Import Assistant Wizard can be accessed from the Tools
menu on the Kinetica toolbar; select Assistants, then Import.
Figure 5-4. Import Assistant Wizard
When using the Import Assistant Wizard, follow the instructions

given in the wizard screens to guide you. You can move back and
forth between the dialogs and change information as needed until
you complete the wizard. You can exit without saving at any
point before completing the wizard.
The first dialog is used to select an import format/source type.

You can select one of the options described in the following table.
Input Format Description
Excel Import data from an Excel spreadsheet.

Supports Excel 97 and later.
ASCII Import data from an ASCII file.

Input Format Description
Database Import data from a database through

Microsoft ODBC (ODBC) technology.
Only database vendors that provide ODBC
drivers for their systems can be imported.
Proprietary Import data that has been entered in a

format proprietary format (such as Siphar or P-
Pharm).
Watson Import data from the Watson LIMS system.

Select studies from a list and see the data
automatically loaded into Kinetica.

Importing Data from This option enables you to import Excel files into the database to
create new Kinetica studies. This section illustrates how to import
Excel Spreadsheets the spreadsheet “DatasetColumn Import Filter.xls” into Kinetica.
1. In Kinetica, from the Tools menu, select Assistants, then

Import…, or click the Import Assistant icon on the
toolbar.
2. When the Import Assistant Wizard starts up you will notice

that the default setting source type is Excel. Keep this default,
and then click Next. The “Import Assistant – Step 1 of 5”
dialog appears. For this example, we will use the default data
layout, Dataset Column.
Figure 5-5. Import Assistant – Step 1 of 5
The selections in this dialog are described in the following

table.
Workbook Displays the selected import file name and path.

The Excel file is selected via the Browse button.

Worksheet Identifies the name of the Excel worksheet

containing the incoming data.
Range Identifies the range of the incoming data within

the selected Excel worksheet.
Data This section specifies the organization of the

Layout incoming data so Kinetica understands the
incoming structure. The options are described in
the following table:
The table below lists the different types of data layouts

recognized by the Import Assistant application.
Dataset Indicates that the selected range of Excel data

Column is stored in column format with unique Time
and Concentration columns for each subject.
XYj Indicates that the selected range of Excel data

is stored in column format with one Time
column at the first column that is the same for
each subject but with different Concentration
columns for each subject
XiYj Indicates that the selected range of Excel data

is stored in column format with time and
various analyte concentration columns for
each subject. This selection allows the user to
choose the number of y columns per
individual profile.
TXiYj Indicates that the selected range of Excel data

is stored in column format with nominal and
actual times and multiple concentration
columns for each subject. This selection allows
the user to choose the number of y columns
per individual profile.

X Allows the user to choose the number of

independent variable columns.
Y Allows the user to choose the number of

dependent variable columns.
Column Indicates that the selected range of Excel

Header columns include a header row. While headers
are not necessary, if they are present, the first
header must be the first cell selected for
export. In addition, the header must be one
line only and there may not be any blank lines
or cells between the header and the data.
3. Click Browse and locate the Excel file called DatasetColumn

Import Filter.xls. This file is located in the Kinetica\Data
folder.
4. The selected file opens in Excel and you are prompted to

select the range of cells you wish to import.
Figure 5-6. Example – Selecting a Range of Cells to import from Excel

5. Using your mouse, select the range of cells from A4 to H244.

Include all displayed values with the column headers. As
illustrated in the figure, do not include the information
“Plasma profiles (mg/l),” “tablet A = 75 mg and tablet B = 75
mg” in your selection.
6. Verify the selected range of cells within the dialog box is

correct and click OK.
7. Excel closes and you the Import Assistant Step 1 of 5 dialog is

now populated with the Excel workbook name, worksheet
name and data range as you selected. Keep the Dataset
Column layout option selected and click Next.
Figure 5-7. Import Assistant Step 1 of 5, with Excel

Workbook, Worksheet and Data Range shown.

8. In the “Import Assistant Step 2 of 5” window, drag the

DrugName field from the top Merge Results edit box to the
second edit box.
9. Next, drag the SbjName field from the Source Columns to

the top Merge Results edit box. You will notice that the
Dataset Name is now equal to “Subj01-A,” a concatenation
of the subject and drug name identifiers in the import file.
This dialog box allows you to set unique identifier for each
subject, period and/or treatment that the subject has
undergone. Click Next.
Figure 5-8. Import Assistant Step 2 of 5
10. The Step 3 of 5 dialog allows you to set up worksheet(s) for

the subject profile. From the Source Columns list, drag and
drop SampleTime and SampleValue to the Source Column
column in the rows X and Y, respectively.
11. Select SampleType for the Import Filter box.
12. Select the Plasma filter for the Plasma worksheet. Click Next.

13. In the Step 4 of 5 dialog, map the numeric and text datasets
to either numeric or text fields. Drag Dose to the source
column for a numeric field and SbjName, DrugName, and
Sequence to the source column for text fields. This step
allows you to set-up demographics, covariables and other data
pertinent to the subjects for the analysis.

14. In the Step 5 of 5 dialog, you may set flags for undetectable,
outlier, missing and error data in the analysis. There are no
identifiers that require filtering for this exercise. The entry of
symbols does not need to be entered under the Dictionary
table. However, you may change the symbols to whatever
status code is set in the original dataset. For example, you
may change the symbol “<” to “BLQ”, “!” to “outlier”,
“#ERR” to “error” depending on the SampleStatus code in
the original Excel file and then choose SampleValue in the
Data column box and SampleStatus in the Status column
box.
The Manage Existing Data box allows you to manage the new
import dataset over the existing datasets by mapping the
unique identifiers corresponding to the two datasets. There
are three options:
• The Append to end box allows you to append the new

import data after the last row of data in the current
worksheet.
• The Append after last value box allows you to append the
new import data after the last value in the corresponding
columns in the current dataset.

• The Delete Existing Data box allows you to overwrite the

new import dataset over the existing datasets by mapping
the unique identifiers corresponding to the two datasets
Figure 5-11. Import Assistant, Step 5 of 5
Note If your source file contains any of the above-mentioned

identifiers (Undetectable, Error, etc.), enter the symbol(s) in the
Dictionary list under the corresponding identifier. If you choose
to replace one of the identifiers provided with a user-defined
symbol, ensure that you copy the remaining system-provided
markers into the row as well then press Enter. This action
prompts Kinetica to insert the automatic data status flag before
the indicated data point inside the Kinetica study. ▲

Object Description
Undetectable Specifies the import code to look for during

the import process to signify a data point is
undetectable. The corresponding internal
Kinetica flag for undetectable data (<) will be
inserted before the data point. During an
analysis, Kinetica will adjust calculations for
the profile according to this status flag. You
can also create your own graphic for this flag.
Outlier Specifies the import code to look for during

the import process to signify that a data point
is an outlier. The corresponding internal
Kinetica flag for outlier data (!) will be
inserted before the data point inside the
Kinetica study. No data is lost or transformed
in this process. During an analysis, Kinetica
will adjust calculations for the profile
according to this status flag. You can also
create your own graphic for this flag
Missing Specifies the import code to look for during

the import process to signify a data point is
missing. The corresponding internal Kinetica
flag for missing data (blank cell) will be
inserted inside the Kinetica study. During an
the profile according to this status flag. You
can also create your own graphic for this flag.
Error An internal code used to avoid floating point

errors in Kinetica.
Data Column This is linked to a column specified in the

Status Column list.

Object Description
Status Identifies the incoming column that contains

Column a data flag. This is linked to a column
specified in the Data Column list (e.g. Code).
You can also enter a user-defined status code.
This code can be a numerical value or one of
the symbols provided in the Dictionary area
of the dialog. If there are no symbols, the data
is imported as usual. If there are symbols
associated with the data, the symbol is
imported into its own status column.
15. Click Finish and the Import Assistant will start processing the
import file for entry into the Kinetica kdb file.
Figure 5-12. Importing Data Dialog
XYj Import Method For the second example, we will use the XYj data layout import
method.
1. In Kinetica, from the Tools menu, select Assistants, then

Import…, or click the Import Assistant icon on the
toolbar.
2. Select XYj in the Data layout area of the dialog (refer to figure
below). The organization of these data is XYj because we have
a single Time column that is identical for all subjects, and
subsequent Concentration columns that are different for
every subject. We have to inform the Import Assistant of this
organization.

3. Click Browse to locate the XnY Import.xls file, which can be

found under the Data subdirectory. Using the mouse, select
the range of cells from A4 to Y14. This dictates to import the
time and concentration values for all subjects. Notice the data
layout. All datasets contain the same time column but
different concentration columns for each subject. Click OK.
Figure 5-14. Example – Selecting a Range of Cells
4. Click Next to the dialog Step 4 of 6. The next Import

Assistant appears, enabling you to drag and drop column

names from the import file to the appropriate

worksheet/column destination inside the Kinetica study.
We did not select a Kinetica template before starting the

Import Assistant. Therefore, the Kinetica study structure in
this dialog displays the objects found in the Normal.kdb
structure (i.e., plasma worksheet with an X and Y column). If
we had selected an existing template or file containing data,
Import Assistant would display the objects of the selected
structure.
5. Drag the Source column called X and Y into the Source

Column of the Dataset columns worksheet corresponding to
X and Y, respectively.

Figure 5-16. Import Assistant Step 4 of 6
You have now specified that all imported time (X) data
should be placed in the Kinetica column called X, and all
concentration (Y) data should be placed in the Kinetica
column called Y during the import process (both will be
found in the Kinetica sample Plasma worksheet). We call this
process Column Mapping. The dialog should appear as
follows:
6. Select the column that contains the data. If a separate column

exists with flags (e.g. codes), specify the column as the status
column, and define the codes in the Dictionary.

Figure 5-17. Import Assistant – Step 5
7. Click Finish. The Import Assistant now processes the

incoming data. The following dialog appears during this
process:
Once the process is complete, the Import Assistant terminates

and the imported data are displayed in Kinetica.

Using the XiYj Import To use the XiYj Import method for importing Excel data:
Method
1. Click the Import Assistant icon located on the toolbar.
The default setting source type is Excel. Click Next.
2. Select XiYj in the Data layout area of the dialog. Specify the
number of analyte or dependent columns for each subject by
entering the number in Y.
The organization of this data is XiYj because we have a single

Time column that is identical for all subjects and multiple
concentration columns for single subject. We have to inform
the Import Assistant of this organization.

3. Select the XiYj layout and enter 2 for Y. Click Next to the
dialog Step 2 of 6.
4. Drag the Source column called X, Y1, and Y2 into the Source
Column of the Dataset columns worksheet corresponding to
X, Y, and the following row respectively.

Figure 5-22. Import Assistant - Step 4
5. Select the column that contains the data. If a separate

column exists with flags (e.g. codes), specify the column as
the status column, and define the codes in the Dictionary.


process:

and the imported data is displayed in Kinetica.
Using the TXiYj Import To use the TXiYj import method:

Method
1. Click the Import Assistant icon located on the toolbar.
The default setting source type is Excel. Click Next.

2. Select TXiYj in the Data layout area of the dialog. Specify the
number of analyte or dependent columns for each subject by
entering the number for X and Y.
Figure 5-26. Import Assistant Step 1 of 3 – TxiYj data layout
The organization of these data is TXiYj because in this

example we have a single Time column that is identical for all
subjects, another subject-specific time column, and multiple
concentration columns for single subject. We have to inform
the Import Assistant of this organization.
3. Click Browse to locate the TXiYj Import.xls file, which can

be found under the Data subdirectory. Using the mouse,
select the range of cells from A4 to J14. This dictates to
import the time and concentration values for all subjects.
Notice the data layout. All datasets contain a same time
column, another subject-specific time column and two
concentration columns for each subject. Click OK.

4. Select the column that contains the data. If a separate

column exists with flags (e.g. codes), specify the column as
the status column, and define the codes in the Dictionary.


process:

and the imported data is displayed in Kinetica.

Importing Data from This option provides the import of data from ASCII files into the
database to create new Kinetica studies.
ASCII Files
1. Load Kinetica.
2. Select Assistants then Import Assistant from the Tools menu

or click the Import Assistant icon on the toolbar. The Import
Assistant wizard appears.
Figure 5-31. Import Assistant Dialog
3. Select ASCII from the Source type list and click Next. The
next Import Assistant dialog appears.

Figure 5-32. ASCII Import Assistant – Selecting Source Files

Dialog
The objects in this dialog are described in the following table.
Object Description
Data Layout Start line: Identifies the first line number

within the incoming structure. The Import
Assistant uses an algorithm that attempts to
locate the logical start line of numeric
information. This is always 1 by default
before opening a file and must be checked
carefully once the incoming file is opened.
The value can be increased or decreased, using
the up and down arrow control, depending
on which line you want to start the import
process.

Object Description
End line: Identifies the last line number

within the incoming structure. The Import
Assistant uses an algorithm that attempts to
locate the logical end line of numeric
information. This is always one by default
before opening a file, and must be checked
carefully once the incoming file is opened.
The value can be increased or decreased, using
the up and down arrow control, depending
on the line you select to end the import
process.
Fields: Identifies the number of fields found

in the lines of data to be imported within the
incoming structure (within the line range
specified via the Start line and End line
identifiers). The Import Assistant uses an
algorithm that reads each line to locate the
field separator identifier. This is always one by
default before opening a file and must be
checked carefully once the incoming file is
opened. The value can be increased or
decreased using the up and down arrow
control, depending on the line you select to
start the import process.
Header: Specifies the presence (9) of header

lines in the import file. Many import files
contain header information that is not part of
the main body of analytical data. The Import
Assistant automatically detects the presence of
the header lines and, if found, selects the
Header check box. If there is a header, there
must be no blank lines between the header
and the data, and the header must be the first
cell selected for import.
Data Format Delimited: Specifies the field separator

characters, e.g. commas, tabs, etc. used in the
data file.

Object Description
Fixed Length: Specifies the field length used

in the data file. You are requested to define
the length of each field in the grid below the
fixed length option.
Selecting the Source File To select a source file to import into Kinetica:
to Import
1. Click Browse and locate the MyAsciiData.txt ASCII file. This
file is found in the Kinetica\data subdirectory. After you open
this standardized ASCII file, information related to the
incoming data structure appears.
Figure 5-33. Example – Selecting an ASCII File to Import
We can now visualize the incoming data structure in the Data

View frame. The Start and End lines have been updated to
reflect the numeric start line as 1 and the numeric end line as
241. In addition, the Import Assistant has found 4 fields in
the numeric lines to import. You can scroll through the Data
View to see the entire contents of the incoming file.

2. Click Next. The next Import Assistant dialog appears. You

can drag and drop column names from the import file to the
merge fields required to create Kinetica dataset names as
follows:
Figure 5-34. ASCII Import Assistant – Creating Dataset

Names
Object Description
Source Contains a list of the column headers found in

Columns the import file. If no column headers are
found, Import Assistant uses automatic labels
and increments them for the number of fields
found in the structure i.e. Col1, Col2, etc. The
ordering of these columns in the list box is
organized by the order they appear in the
import file. Then, the first field found (called
DrugName in our case) is automatically placed
in the first Merge Result field. This is because
most import structures are ordered with the
first column as the subject identifier, and is
designed to help quickly in the merge process.

Object Description
Merge Contains a maximum of five ordered fields

Results where source columns can be dragged to create
the final merged dataset name. The sixth field
contains the resulting label created from a
concatenation of the data contents found in
each merge field.
3. Using your mouse, drag the DrugName field from the first
Merge Results field to the second field (if you are using the
example file).
4. Drag the SbjName field from the Source Columns list box to
the first Merge Results field that should be empty (if you are
using the example file). Notice that the Dataset Name is now
equal to "Sbj01-A" which represents the first row of data and
is a concatenation of the subject and drug name identifiers in
the import file. You are encouraged to select as many dataset
identifiers as possible to ensure data integrity. The dialog
appears as follows:
Figure 5-35. ASCII Import Assistant – Selecting Dataset

Identifiers

Note Import Assistant places a hyphen (-) between the two

field values for easier understanding once the data is opened
inside Kinetica. ▲
5. Click Next. The next Import Assistant dialog appears,

enabling you to drag and drop column names from the
import file to the appropriate worksheet/column destination
inside the Kinetica study.
Figure 5-36. Import Assistant – Selecting Worksheet

Columns
We did not select a Kinetica template before calling the

Import Assistant; therefore, the Kinetica study structure in
this screen displays the objects found in the Normal.kdb
structure (i.e. Plasma worksheet with an X and Y column). If
structure.
The objects in this dialog are described in the table below.

Object Description
Source Contains a list of the column headers found in

Columns the import file. If no column headers are
found, Import Assistant uses automatic labels
and increments them for the number of fields
found in the structure i.e. Col1, Col2, etc. The
ordering of these columns in the list box is
organized by the order they appear in the
import file. Then, the first field found (called
DrugName in our case) is automatically placed
in the first Merge Result field. This is because
most import structures are ordered with the
first column as the subject identifier and is
designed to help speed the merge process.
Dataset Typically a series of time-dependent data values

Columns that are either imported as raw data or
computed output during a Kinetica analysis.
Examples are Time, Concentration, AUC,
AUMC, etc.
The Dataset Columns spreadsheet contains a destination

column where the import column headers can be dragged to
(a) map incoming column data into pre-defined Kinetica
template structure, or (b) map incoming column data into a
user-defined Kinetica template structure.
6. Drag the Source column called SampleTime into the empty

destination Source Column cell that is adjacent to the X
column.
7. Drag the Source column called SampleValue into the empty

destination Source Column cell that is adjacent to the
Kinetica Y column.
You have just specified that all imported time data should be
placed in the column called X and all concentration data
should be placed in the column called Y during the import
process (both will be found in the Kinetica Plasma
worksheet). We call this process Column Mapping. The
dialog appears as follows:

Figure 5-37. ASCII Import Assistant – Creating Kinetica

worksheet Columns
8. Click Next. The next Import Assistant appears, enabling you

to drag and drop column names from the import file to their
study/field destination inside the Kinetica template.
Figure 5-38. Import Assistant – Creating Kinetica Import File

Names

Object Description
Source Source Columns contain a list of the column

Columns headers found in the import file. If no column
headers are found, Import Assistant uses
automatic labels and increments them for the
number of fields found in the structure i.e.
Col1, Col2, etc. The ordering of these
columns in the list box is organized by the
order they appear in the import file. Then, the
first field found (called DrugName in our case)
is automatically placed in the first Merge Result
field. This is because most import structures are
ordered with the first column as the subject
identifier and is designed to help quickly in the
merge process.
Dataset Typically a series of time-dependent data values

Columns that are either imported as raw data or
computed output during a Kinetica analysis.
Examples are Time, Concentration, AUC,
AUMC, etc.
Dataset Dataset fields are typically a series of non-time

Fields dependent data values, which are either
imported as raw data or computed output
during a Kinetica analysis. Examples are AGE,
WEIGHT, T1/2, Cmax, etc.
The Dataset Fields spreadsheet contains destination numeric

and text fields where the import column headers can be
dragged to (a) map incoming column data into pre-defined
Kinetica template structure or (b) map incoming column data
into a user-defined Kinetica template structure.
9. In our example import file, the SbjName and DrugName

fields are both text fields. Drag the Source column called
SbjName into an empty destination Source Column cell that
is adjacent to the first empty Kinetica Text field column.

10. Drag the Source column called DrugName into the next
successive empty destination Source Column cell.
You have specified to the Import Assistant that all imported

treatment and subject identifier data should be placed in the
Kinetica dataset text fields called SbjName and DrugName,
both found in the Kinetica Dataset pane. We call this process
Field Mapping. The dialog appears as follows:
Figure 5-39. ASCII Import Assistant – Field Mapping

Figure 5-40. ASCII Import Assistant – Specifying Import

Filter Identifiers
Object Description

the import process that signifies a data point is
Kinetica study. No data is lost or transformed
according to this status flag.

an outlier. The corresponding internal
Kinetica flag for outlier data (!) will be inserted
before the data point inside the Kinetica study.
No data is lost, or transformed in this process.
During an analysis, Kinetica will adjust
calculations for the profile according to this
status flag.

Object Description

the profile according to this status flag.

errors in Kinetica.
Data Column Identifies the incoming column that contains

data that is flagged. This is linked to a column
specified in the Status Column list.
Status Identifies the incoming column that contains a

Column data flag. This is linked to a column specified
in the Data Column list. You can also enter a
user-defined status code. This code can be a
numerical value or one of the symbols
provided in the Dictionary area of the dialog.
If there are no symbols, the data is imported as
usual. If there are symbols associated with the
data, the symbol is imported into its own
status column.
Note If your source file contain any of the above-

mentioned identifiers (Undetectable, Error, etc.), enter the
symbol(s) in the Dictionary list under the corresponding
identifier. If you choose to replace one of the identifiers
provided with a user-defined symbol, ensure that you copy
the remaining system-provided markers into the row as well
then press Enter. This action prompts Kinetica to insert the
automatic data status flag before the indicated data point
inside the Kinetica study. ▲
11. Do not identify any flags for this example. Click Finish and
the Import Assistant processes the incoming data. Once the

process is complete, the Import Assistant terminates and

Kinetica displays the imported data.

Importing Data from The Import Data from a Database option enables you to import
data from external databases to create new Kinetica studies. Only
Databases databases that support the Microsoft ODBC technology can be
imported.
1. Load Kinetica.

Figure 5-41. Import Assistant – Importing from a Database

Figure 5-42. Import Assistant – Selecting a Source

Database
Object Description
Available Provides a visualization of the selected database

Views views. This is useful for quickly understanding
the incoming database structure.
Data Preview A check box that, if selected, displays a preview

of the data contained in the currently selected
database view.

Selecting a Database for To select a database to import data into Kinetica:

Data Import
1. Click Select to call the Microsoft ODBC engine. The Select
Data Source dialog appears.
Figure 5-43. Select Data Source – Machine Data Source

Tab
2. Click the Machine Data Source tab. If ODBC has been

installed on your PC and some Machine Data Sources have
been created, you should see a list of drivers. Double-click on
the Microsoft Access (Access) driver. If you do not see a list of
drivers, or Access is not in your list, and ODBC has been
installed, you can create one by clicking New and following
the on-screen instructions.
Note At this point you will ascertain if ODBC has been

installed with Microsoft Windows 95 or NT 4.0. If you can
not proceed further than this point in the exercise, please
consult your IT personnel or Microsoft Windows
documentation for further information related to installing
ODBC, and then try the exercise again. ▲

3. Once you have double-clicked on the Access machine data

source the Login dialog appears if your database has security
enabled. Databases are usually protected by passwords;
however, for this exercise we did not protect the database.
The Select Database dialog appears.
Figure 5-44. Select Database Dialog
4. Locate the Access database file called ImportAccess.mdb. This

file is in the Kinetica\data subdirectory. The Import Assistant
screen is updated with the database views found in the
selected file. Some of these database views contain the
time/concentration information required for import into a
Kinetica study.

Figure 5-45. Import Assistant – Selecting a Database View
Figure 5-46. Import Assistant – Selecting a Source

Database

enabling you to drag and drop column names from the
import file to the merge fields required to create Kinetica
dataset names.

Figure 5-47. Import Assistant – Creating a Dataset Name
Object Description
Source Contains a list of the table names found in

Columns the selected database view. The table names in
the Source Columns list box are organized in
the order they appear in the database view.
The first table name found (called DrugName
in our example) is automatically placed in the
first Merge Result field.
Merge Results Contains a maximum of five ordered fields

where source columns can be dragged to
create the final merged dataset name. The
sixth field contains the label created as a result
of a concatenation of the data contents found
in each merge field.
6. Using your mouse, drag the DrugName field from the first
Merge Results field to the second Merge Results field.
7. Drag the SbjName field from the Source Columns list to the
first Merge Results field, which should be empty. Notice that
the Dataset Name is now equal to "Sbj01-A" which

represents the first row of data. It is a concatenation of the

subject and drug name identifiers in the import file. The
Figure 5-48. Import Assistant – Creating a Dataset Name
Note Import Assistant places a hyphen (-) between the two

field values for easier understanding once the data is opened
inside Kinetica. ▲

enabling you to drag and drop table names from the import
file to their worksheet/column destination inside the Kinetica
study.

Figure 5-49. Import Assistant – Creating Worksheet

Columns
We did not select a Kinetica template before calling the

Import Assistant; therefore, the Kinetica study structure in
this screen displays the objects found in the Normal.kdb
structure (i.e. plasma worksheet with an X and Y column). If
structure.
Object Description
Source Contains a list of the table names found in

Columns the database view.
Dataset The Dataset Columns spreadsheet contains a

Columns destination column where the import column
headers can be dragged to: (a) map incoming
column data into pre-defined Kinetica
template structure, or
(b) map incoming column data into a user-
defined Kinetica template structure.

9. Drag the Source column called SampleValue into the empty

destination Source Column cell that is adjacent to the Y
column.
You have specified to the Import Assistant that all imported

time data should be placed in the X column, and all
concentration data should be placed in the Y column during
the import process (both will be found in the Kinetica sample
Plasma worksheet). We call this process Column Mapping.
The dialog appears as follows:
Figure 5-50. Import Assistant – Column Mapping Dialog

Figure 5-51. Import Assistant – Creating Kinetica Dataset

Numeric and/or Text Fields
Object Description
Source Contains a list of the table names found in the

Columns database view.
Dataset The Dataset Fields spreadsheet contains

Fields destination numeric and text fields. The import
column headers can be dragged to:
map incoming column data into pre-defined

Kinetica template structure, or
map incoming column data into a user-defined

Kinetica template structure.
A dataset field is typically a series of non-time dependent data

values that are either imported as raw data or computed
output during a Kinetica analysis. Examples of dataset fields
include: AGE, WEIGHT, T1/2, Cmax, etc. In our example
import file, the SbjName and DrugName fields are both text
fields.

10. Drag the SbjName Source column into the empty destination
Source Column cell in the Dataset fields area of the dialog,
adjacent to the first empty Kinetica Text field column.
11. Drag the DrugName Source column into the next empty
destination Source Column cell.
You have specified that all imported treatment and subject

identifier data should be placed in the Kinetica study text
fields called SbjName and DrugName, both found in the
Kinetica Study pane. We call this process Field Mapping. The
Figure 5-52. Import Assistant – Field Mapping

Figure 5-53. Import Assistant – Specifying Import Filter

Identifiers
Object Description

Kinetica study. No data is lost, or transformed

status flag.

Object Description


errors in Kinetica.
Data Column Identifies the incoming table name that

contains flagged data. This is linked to a table
name specified in the Status Column field.

status column.

12. Do not identify any flags for this example. Click Finish. The
Import Assistant processes the incoming data. Once the



Importing Data in To import data in a proprietary format into Kinetica:

Proprietary Formats
1. Load Kinetica.

3. Select Proprietary format from the Source type list and click
Next. The next Import Assistant dialog appears.
Figure 5-54. Import Assistant – Proprietary Format Import
4. Select the file you want to import and click Next.
• If you selected an .xpd file, select the file type from the
Select XPD Type dialog and click OK.
• If you selected a .kdb file, proceed to Step 6.
The next Import Assistant dialog appears.

6. Drag and drop column names from the available columns list
to create the identifiers that will make up your dataset.
7. Click Next. The next Import Assistant dialog appears.
Note If you are importing Kinetica or P-Pharm data,

Kinetica recognizes this structure so it is not necessary to drag
the column names. The Subject name followed by the Drug
Name should appear under the Merge Results list. ▲
8. Further define your dataset by dragging and dropping names

from the source columns list.
9. Click Next. The next Import Assistant dialog appears.
10. For this example, drag and drop Extravascular.T and

Extravascular.C from the Source Columns list to the x and y
columns in the Dataset columns area of the dialog.

Figure 5-56. Import Assistant – Creating Kinetica Worksheet

Columns
11. Further define the dataset fields by creating the appropriate

numeric and text fields.
Figure 5-57. Import Assistant – Defining the Dataset Fields


enabling you to specify import filter identifiers to set
automatic data status flags inside the Kinetica template.
Figure 5-58. Import Assistant – Specifying Import Filter

Identifiers
Object Description

Kinetica study. No data is lost, or transformed

Object Description

status flag.


errors in Kinetica.
Data Column Identifies the incoming table name that

contains flagged data. This is linked to a table
name specified in the Status Column field.

status column.



13. Do not identify any flags for this example. Click Finish. The
Import Assistant processes the incoming data. Once the

Importing Data from To import data from Watson LIMS:

Watson LIMS
1. Load Kinetica.

3. Select Watson from the Source type list and click Next. The
Import Assistant dialog appears.
4. Select the Watson study you want to import from the

available list and click Next. Kinetica will display the
following screen through which you will select the data
source.

Figure 5-60. Select Data Source Dialog
5. Select the appropriate data source from the screen and click
OK. You will be prompted to logon to the Oracle database
for Watson.
Figure 5-61. Oracle Logon Dialog
6. Select the Server Name using the drop down menu.
7. Enter your User Name and Password for the Oracle database
and click OK. Kinetica will display the Import Assistant
Window again, through which you simply select information
you wish to import and click Finish.

Figure 5-62. Import Assistant Study Selection Window

Importing Kinetica supports the import of data files from P-Pharm, Pharm-
ABS, Pharm-NCA, SIPHAR (DOS); SIPHAR (Win), PCNonlin
Miscellaneous Data and WinNonlin.
Kinetica uses a private four-dimensional database for data storage

that ensures security and data integrity. The database can handle
simple and complex study structures. Many other software
programs use an ASCII-based file structure that can be read by
any text editor. This enables the successful import of data files
into Kinetica.
Importing xpd Files To import xpd files:
1. Load Kinetica.
2. Select Open from the File menu. The Open File dialog
appears. By default the Data subdirectory is displayed.
3. Navigate through the directory structure to find the directory

where your .xpd files are stored.
Note Kinetica will not display any xpd files until you enter
*.xpd in the File Name field. ▲
4. Click Open. The window refreshes and displays the xpd files
found in the selected directory.
5. Select the xpd file you want to import and click Open. The
selected file is opened, renamed as a kdb file and displayed in
the Kinetica workspace.
The original xpd file you opened is not altered or deleted.

Kinetica makes a copy of the file and translates it into a kdb file.
When you are finished reviewing and/or editing the imported

file, you can close it. At this point you are prompted to save the
file. You must save the file in order to keep the imported copy of
your data; otherwise Kinetica discards the file contents.

Importing SIPHAR Files To import SIPHAR files (DOS or Win):
1. Load Kinetica.
2. Select the Macro Editor from the Study pane.
3. Select Open from the File menu to load the Import Siphar
Dos.kmd.
4. Select Macro Editor from the Tools menu to execute the

macro.
5. Navigate through the directory structure until you find the

directory where your SIPHAR/DOS files (*.dB) are stored.
Note Kinetica will not display any of these files until you
enter the file extension in the File Name field and click Open.
The window refreshes and displays any Cipher/DOS files
found in the selected directory. ▲
6. Select the appropriate file and click Open. The selected file is
opened, renamed as a kdb file and displayed in the Kinetica
workspace. If a worksheet is not selected, a deletion will not
occur.
7. When you are finished reviewing and/or editing the imported

file, you can close it. At this point you are prompted to save
the file. You must save the file now in order to keep the
imported copy of your data; otherwise Kinetica discards the
file and its contents.

Importing PCNonlin Files Kinetica automatically translates PCNonlin data and model data
(which is stored in the file) into the Kinetica structure, when the
files are imported.
1. Launch Kinetica.
2. Select Macro from the Tools menu. The Macros dialog

appears.
3. Click the Import PCNonlin button on the toolbar.
4. Click Run. The File Open dialog appears.
Note Kinetica will not display any *.CMD files until you
enter the file extension in the File Name field and click Open.
The window refreshes and displays any PCNonlin (*.cmd)
files found in the selected directory. ▲
5. Select the appropriate file and click Open. The selected file is
opened, renamed as a kdb file and displayed in the Kinetica
workspace. The original file you opened is not altered or
deleted. Kinetica makes a copy of the file and translates it into
a kdb file.
When you are finished reviewing and/or editing the imported

file, you can close it. At this point you are prompted to save the
file. You must save the file now in order to keep the imported
copy of your data; otherwise Kinetica discards the file and its
contents.

Exporting Data to Use this option to export your data to external databases. Only
data supporting Microsoft ODBC technology can be exported.
External Databases
1. In Kinetica, from the Tools menu, select Assistants then
Export. The Export to Database dialog appears.
Figure 5-63. Export Dialog to select the type of file
2. Select the file type for the export then click next.
3. Select the fields to export. The left hand box shows the study-
level fields while the right hand box lists the worksheet
column fields. Check the Append Worksheet Name box to
include the worksheet name in the column header in the final
exported file.

Figure 5-64. Select Field Dialog
4. Click Export.
5. Type the name of the outgoing file in the File name field.
Figure 5-65. Set Data file name Dialog

6. Click Save.
Exporting Data to Kinetica offers two methods for automatically exporting data to
Microsoft Word and Microsoft Word (Word) and Microsoft Excel (Excel). These
options can be found on the menu bar as follows:
Microsoft Excel
Figure 5-66. Export Options
Kinetica uses the Normal.dot that is loaded by default in your

version of Word. The format of the exported results depends on
how styles are defined in your Normal.dot file. The tabulation
may look skewed when you export to Word. Adjust the tab stops
in Word to reorganize the data, as required.
Note In order to export data to Excel successfully, ensure that

you specify one symbol for decimals (e.g. “,”), and a different
symbol for digit grouping (e.g. “.”). Symbols are defined in the
Numbers tab of the Region Options dialog, located in your
Windows Control Panel. ▲
To export data to Word or Excel:
1. Load Microsoft Word or Excel.
2. Load Kinetica.
3. Run an analysis or open a dataset with raw data values.
4. Using the mouse, highlight the columns or rows you want to

export from the sample view in the Dataset pane.
5. Choose Report Setup from the File menu. The Report Setup
dialog appears.

Figure 5-67. Report Setup Dialog
6. Click Set Destination or double click on the appropriate

destination in the lower part of the dialog (in this case Word
97). The Open dialog appears.
7. Name the file and path and click OK to exit the dialog and
return to the Report Setup dialog. The information is
displayed in the Select Output area of the Report Setup
dialog.
8. Highlight the required columns and variables and select

Export to Word or Export to Excel from the File menu. If
you are exporting to Word, you can also select one of the
following Calculate buttons to generate a full report:
Figure 5-68. Calculate Buttons
9. Switch to Microsoft Word or Excel. The information you

exported is displayed.

Report Log Files Kinetica writes specific information on the transformation of data
into a log file. This information is copied to the Info view for
each dataset (subject) after you run each analysis. If you modify
specific data values and/or method options, Kinetica will
automatically update the necessary parts of the information/log
file.
The transformation of data into a log file is very useful because it

gives you access (at all times) to the program during calculations.
This facility is not a full audit trail but it does help you to
understand the way the data was analyzed and details the
revisions that have been made.
In addition to writing this information to the Info view, Kinetica

also creates a log file of all the collective information on the study
including the transformations of the data. This file is called
report.txt and is automatically created as a text file in the
Kinetica\Reports subdirectory.
To change the name of this file and the directory where it is

stored:
1. Load Kinetica. Do not open any files.
2. Select Report Setup from the File menu. The Report Setup
dialog appears.

Figure 5-69. Report Setup Dialog
3. Click on the Report item in the Select Output area of the

dialog.
4. Click Set Destination. The Open dialog appears displaying

the Kinetica\Reports directory.
5. Navigate to the appropriate directory and enter the name of

the file in the File Name field.

Notes

6. Graphs in Kinetica
Kinetica offers a variety of ways to examine and present your data
graphically. All graphs can be incorporated into Microsoft Office
applications.

Graphs in Kinetica
Working with Graphs Kinetica graphs can be created manually or automatically. You
can generate standard graphs or insert a graph method. This
inserted method type of graph will be plotted each time you run
an analysis. Many graph attributes can be modified; outlier and
non-detectable data points can be flagged. You can create your
own libraries of standardized graph templates and quickly apply
them to single or multiple graphs.
Kinetica includes a powerful graph gallery which enables you to

collect, edit and save multiple sets of graphs simultaneously.
Graphs can be reorganized inside the gallery, previewed before
printing, saved to the Graph Gallery, and/or exported to Word.

Graphs in Kinetica
Starting the Chart With a .kdb file is open in Kinetica, you can start the Chart
Wizard by selecting Tools from the menu bar, then Chart
Wizard Wizard:
Figure 6-1. Opening Chart Wizard from the Kinetica Tools menu
Once the option is selected, you will be prompted that the study
is being opened and that the Study Tree is being created.
Chart Wizard Step 1: The first step in the Chart Wizard is to select the columns to be
Select X and Y Axis, plotted. From the directory tree in the left pane of the Chart
Wizard, drag and drop the column names for the data to be
Mean Curve and Overlay
plotted along the x-axis and y-axis into the X Variable and Y
Plot Variable boxes, respectively.
You may also use Chart Wizard to plot the standard deviation of
your data columns, displayed as error bars on your final chart. To
include standard deviation data, each Y-variable MUST have a
corresponding Up and Down value defined in the dataset. Drag
the column representing the upward error to the Up box and
drag the column for the downward error to the Down box.

Graphs in Kinetica
Figure 6-2. Chart Wizard Step 1 – Selecting data columns for the X and Y axes, standard deviation
in Y.
If you check the Create Mean Curve checkbox, you will be

presented with an option to group the data by dragging and
dropping any variable presented on the left window.

Graphs in Kinetica
Figure 6-3. Chart Wizard Step 1 – Create a Mean Curve
Chart wizard allows you to have up to five sets of X-Y data

overlaid on a single plot. Your plot can contain two separate Y-
scales; one on the left side of the plot and one on the right.

Graphs in Kinetica
Figure 6-4. Chart Wizard Step 1– Create Overlay Plot
Note If you check the box to make an overlay plot you must
provide the X and Y variable names in order for the plot to be
generated. ▲
The X-variable often has discontinuities or large gaps. For

example, a data set could only have sampling data from the first
few minutes after each dose that is given once a day. In such a
case, when there are large gaps in the time values, creating a line-
graph that joins all of the data points would be undesirable. The
“Threshold for discontinued X-axis” option enables you to not
join Y-variable data points that have relatively large gaps in their
corresponding X-axis data. You can choose to provide a value for
the threshold at which the plot will display a discontinuity (by
placing a point in the X-axis) or let Chart Wizard determine the
same.

Graphs in Kinetica
Figure 6-5. Chart Wizard Step 1 – Threshold for Discontinued X-Axis
Note The Chart Wizard does not check the validity of what
you are trying to graph. You need to make sure that you select the
correct variables and the correct settings to allow the Chart
Wizard to produce the expected results. ▲
Chart Wizard allows you to select the option to Stagger Plots on

a Graph. When Y variable data for the different datasets are very
close to each other, the resulting plot may be difficult to read.
The Stagger Plots option separates the plots so that they are easier
to distinguish from one another. You may choose to let Chart
Wizard to determine the spacing for the staggered graph for
successive datasets, or you may select the Manual Override
option. When using the Manual Override option, you must
provide a value in the available text box that will be added to each
X-value for the staggered graph (see figure below).

Graphs in Kinetica
Figure 6-6. Chart Wizard Step 1– Stagger Plots on a Graph
Once you have finished setting the appropriate parameters for

your graph, click Next to proceed to Step 2 of the Chart Wizard.

Graphs in Kinetica
Chart Wizard Step 2: The second step of the Chart Wizard asks you to select which
Selecting Datasets of datasets you wish to see on your graph. You may select all
datasets with the Select All checkbox, or choose individual
Interest
datasets by clicking on the dataset name. Multiple datasets may
be selected by pressing the CTRL key while clicking on the
dataset names.
Figure 6-7. Chart Wizard Step 2 – Selecting a Dataset
Once you have selected the appropriate datasets, click Next to

proceed to Step 3 of the Chart Wizard.

Graphs in Kinetica
Chart Wizard Step 3: The third step of the Chart Wizard allows you to set the sorting
Selecting Sort Criteria criteria. Select the sort criteria from the left pane using the drag
and drop function.
Figure 6-8. Chart Wizard Step 3 – Selecting Grouping Criteria
Variables can be removed by selecting the variable and clicking

the Remove Selected button. The button is not active unless a
variable has been selected from the existing list.

Graphs in Kinetica
Chart Wizard – Step 4 The fourth step of the Chart Wizard allows you to select filters to
Selecting Filters be applied to the results by constructing logical AND/OR
conditions. Below is the default view of Step 4 (without having
selected an Overlay option in Step 1).
Figure 6-9. Chart Wizard Step 4 – Selecting Filters
1. Select the appropriate variables by using the drag and drop

function.
2. Select the appropriate operator using the drop down menu

provided.
3. Select a value from the drop down menu following the

selected operator or, if none exist, enter a value into the text
box provided.

Graphs in Kinetica
Note This menu is populated based on the Variable chosen.

Not all Variables will have information to populate this
menu. ▲
4. Select the AND of OR button to add the condition to the

text field below.
5. Repeat the steps above until all of your conditions have been
entered.
6. Click Next to proceed to Step 5 of the Chart Wizard.
Note You can remove any Conditions by selecting the

Condition and then clicking on the Remove button. ▲
If you had chosen the Overlay option at the Step 1, Step 4 will
appear as follows:

Graphs in Kinetica
Figure 6-10. Chart Wizard Step 4 – Selecting Filters - Overlay Example
Follow the same steps as stated above when creating an Overlay

Plot filter. The application does not require that you enter filter
information in the Overlay Plot section included on this screen.
When filter information has been entered successfully, click Next
to proceed to Step 5 of the Chart Wizard.

Graphs in Kinetica
Chart Wizard Step 5: The fifth and final step of the Chart Wizard sets the chart title
Setting Chart Properties and/or subtitle for the graph you are creating. Enter the title into
the text box provided and click the Chart button.
Figure 6-11. Chart Wizard Step 5 – Setting Chart Properties
Clicking the Chart button completes the chart as designed

through the Chart Wizard. The following image is an example of
a completed chart. The vertical lines in the graph represent the
Standard Deviation.

Graphs in Kinetica
Figure 6-12. Example 1– A finished chart.
From the left side of the chart window you can toggle specific
plots on and off by selecting the check box next to the dataset
name or show all plots by checking the Show All checkbox.
The Error Bars check box allows you turn the Standard Deviation
error bars on or off.
The Reset button returns the chart view to the original settings.
The Finish button closes Chart Wizard and gives you the option
to save your settings prior to closing. If you choose to save the
settings, the chart will automatically reopen when you select
Tools | Chart Wizard.

Graphs in Kinetica
Sending the Graph to You may send the graph to the Kinetica Gallery by right-clicking
Kinetica Gallery in the graph area of the Chart Wizard and selecting Send Graph
to Kinetica Gallery.
Figure 6-13. Chart Wizard Pop-up Menu
You may choose to send all graphs in Chart Wizard to the

Kinetica Gallery by selecting Send All Graphs to Kinetica Gallery
from the pop-up menu.
Note Not all of the formatting features in the Chart Wizard

plot are transferred to the graph in the Kinetica gallery, because of
inherent differences between the Kinetica graphs and Chart
Wizard plots. ▲

Graphs in Kinetica
Hot Graphs A hot graph is a graph built within Kinetica. These graphs are
linked to data present in your study and appear in Views within
the Kinetica panes. Each time your data changes, these graphs are
automatically updated. Kinetica includes three hot graphs:
• Dataset Graph
• Spaghetti Plot
• Mean Curve
The Dataset Graph is found in the Dataset pane; the Spaghetti

Plot and Mean Curve are located in the Study pane. To access the
graph(s), click on the corresponding icon and Kinetica will
display the graph. Below is an example of the Dataset Graph.
Figure 6-14. Hot Graph Example - Dataset Graph

Graphs in Kinetica
Dataset Graph The Dataset graph is hot-linked to time-series data. By default,

when a study file is opened, the plot uses the left two columns for
the first subject, found in the first sample matrix, to create the
graph. The view appears as follows:
Figure 6-15. Example - Dataset Graph
Dataset Graph Options A right-click anywhere on the Dataset Graph displays the
following menu options:
Figure 6-16. Dataset Graph Menu Options
The options are described in the following table.

Graphs in Kinetica
Option Description
Select X,Y Displays the Select Data dialog that enables you to over-ride the columns used
to display the Dataset Graph All Variables computed during an analysis.
The Column X and Column Y list boxes display all available matrices and
columns within the study. Select a Matrix.ColumnName for both the X and Y
columns, click OK, and the Dataset Graph is updated.
Note: X and Y must be from the same worksheet. ▲
Graph Properties Displays a cascade menu.
Show Sets Legend Show/hide the legend associated with the plot
Show Points Show/hide the points legends associated with the description of the markers
Legend
Add free comment You can add a text comment to your graph.
Profile Properties You can modify a datapoint symbol, status, line, AUC and error bars. Once
the Profile Properties dialog is open, modifications can be applied to the
selected dataset and adjustments can be made to the remaining datasets by
scrolling through the graphs. You can select Properties to access more settings.
Ensure that you click Apply then OK to save your selections.

Graphs in Kinetica
Option Description
Note The Common properties check box is used to set the marker and line
color to black instead of blue and red. ▲
Send to Gallery Once Send to Gallery option is selected, you can choose to send the current
dataset graph or all dataset graphs to the Gallery.
Save As Graph Saves the current style to a graph template file (filename extension of a graph
Template template file is *.kgr).
Load Graph Applies the style in an existing graph template file to the selected
Template
Save Graph As Saves the graph in Bitmap (*.bmp), Metafile (*.wmf) or JPEG (*.jpg) formats.
Apply Axis Scale Selecting this feature allows the axis scale options selected for one dataset
to All Dataset graph applied to all existing dataset graphs in a study.
Graphs
Note The axis scale options have to be accessed first before selecting this
feature. Right click on either axis to see the list of options. Once the
adjustments are made, right click again anywhere on the graph and select
Apply Axis Scale to All Dataset Graphs. ▲
If there are multiple subjects in your study, you can use the
dataset scrollbar in conjunction with this graph view to browse
the dataset graphs within the current study. The dataset scroll bar
can be found on the Kinetica toolbar.

Graphs in Kinetica
Figure 6-17. Dataset Scrollbar

Graphs in Kinetica
Spaghetti Plot The Spaghetti Plot is hot-linked to time-series data. By default,

when a study file is opened this plot uses the left two columns for
all subjects, found in the first sample matrix, to create the graph.
A legend is plotted to the right of the graph to identify the
individual subject data. The view appears as follows:
Figure 6-18. Example - Spaghetti Plot

Graphs in Kinetica
Spaghetti Plot Options A right-click anywhere on the Spaghetti Plot displays the
following menu options:
Figure 6-19. Spaghetti Plot Menu Options
For a description of these options, see this chapter, section,

“Dataset Graph Options.”

Graphs in Kinetica
LZ Graph You can now access the LZ Graph from Methods | LZ Graph:
Figure 6-20. LZ Graph

Graphs in Kinetica
Mean Curve The Mean Curve is hot-linked to time-series data. By default,

when a study file is opened this plot uses the left two columns for
all subjects, found in the first sample matrix, to compute the
mean graph.
Kinetica includes an option for plotting Mean Curves and at the

same time outputs the relevant computed statistics and summary
table. The Mean Curve dialog enables you to plot three different
mean curves on the same plot (overlay graph) or a mean curve by
Group. A Mean Curve graphical view linked to the data in real-
time is also provided in the Study pane. The view appears as
follows:
Figure 6-21. Mean Curve Chart

Graphs in Kinetica
Mean Curve Options A right-click anywhere on this graph displays a series of menu
options:
Figure 6-22. Mean Curve Menu Options
The options are explained in the following table.
Option Description
Mean Standard: Displays the Mean Curve dialog.

Curve
This dialog is used to override the number of
overlaid graphs (maximum is three), the
columns used to display the mean curve, the
mean type, the error type, and the title.
By Group: Displays the Mean Curve by Group

dialog.
This dialog is used to override the columns used

to display the mean curve, the group identifier,
the mean type, the error type, and the title.
For a description of the remaining options, see this chapter,

section “Dataset Graph Options.”

Graphs in Kinetica
Plotting Mean Curves Kinetica has a “hot graph” mean curve that is linked to the data
without Statistics in real-time. As the data changes, Kinetica amends the mean
curve within this view. You can plot up to three different mean
curves on an overlay and create a mean curve by group.
No statistics report is available with this hot view.
To plot mean curves:
1. Launch Kinetica.
2. Click Open from the File menu.
3. Select the Group Table.kdb file, found in the

Kinetica\example\statistics subdirectory.
4. Click OK. Notice that the file contains data for 24 subjects
across two treatments (two-way crossover).
5. Select the Study pane.
6. Click the Mean Curve item. The mean curve appears in the
view.

Graphs in Kinetica
Figure 6-23. Example – Mean Curve Display
Try changing some of the data values in the Dataset pane and
return to the mean curve to see the updated graph.
Plotting Mean Curves by To plot mean curves by group without statistics:

Group without Statistics
1. Complete the procedure for plotting mean curves without
statistics (see this chapter, section, “Plotting Mean Curves
without Statistics”).
2. Right-click on the graph and select Mean Curve then By

Group from the popup menu. The Mean Graph by Group
dialog appears.
3. You can select the group and sort variables by clicking on

them. You can select multiple group and sort variables by
pressing the Ctrl key, while you click on each desired variable.

Graphs in Kinetica
4. You can insert variables into the Group Label or Graph Title
by using ‘&’:
5. The Mean type for the graph can be set to Mean (arithmetic
mean), Geometric Mean, or Harmonic Mean.
6. The Error type can also be specified to be SD, SEM, or

None.
7. You can type in a Graph Title, leave it blank, or select the

Kinetica default title.
8. The created plot can then be saved to a gallery, by setting the

Write to Saved Gallery option.
Figure 6-24. Mean Curve by Group Dialog
9. Specify the various options, as required and click OK. The

plot appears.

Graphs in Kinetica
Figure 6-25. Example – Mean Curve by Group
Note This graph is hot and will therefore change as your

data changes. ▲
Plotting Mean Curves Kinetica can also create mean curves using a menu option. The
with Statistics generated graphs are sent to the Graph Gallery. The graphs are
created with full statistics that can be sent to Word if the correct
Report Setup option has been specified. These are not hot graphs.

Graphs in Kinetica
Plotting Standard or In the example below we will plot a standard mean curve using
Overlay Mean Curves 24 datasets via the menu option that creates an output report on
the computed statistics. This option allows you to plot up to
with Statistics
three different mean curves on an overlay graph.
1. Launch Kinetica.
2. Click Open from the File menu.
3. Select the Group Table.kdb file, found in the

\kinetica\example\statistics subdirectory.
4. Click OK. Note that the file contains data for 24 subjects
across two treatments (two-way crossover).
5. Select the Study pane.
6. Select Mean Curve and then Standard from the Statistics

menu. The Mean Curve dialog appears.
Figure 6-26. Mean Curve Dialog

Graphs in Kinetica
7. Select Plasma.Time in the X = list box located in the First

Graph area of the dialog.
8. Select Plasma.Conc from the Y = list box located in the First

Graph area of the dialog.
9. Select Mean in the Mean Type area of the dialog.
10. Select SD in the Error Type area of the dialog.
11. Enter a title in the Graph Title field and click OK.
The mean curve is displayed with error bars in the Graph Gallery.
The respective mean statistics (as a summary) are written in the
Info worksheet of the Study pane. The mean table results and
table will output to Word automatically if you selected Word in
the Report Setup option.

Graphs in Kinetica
Plotting Mean Curves by You can access the Mean Curve By Group function through
Group with Statistics Statistics>Mean Curve>By Group:
Figure 6-27. Mean Curve by Group Dialog
1. You can select the group and sort variables by clicking on

them. You can select multiple group and sort variables by
pressing the Ctrl key, while you click on each desired variable.
by using ‘&’:
3. The Mean type for the graph can be set to Mean (arithmetic
mean), Geometric Mean, or Harmonic Mean.
4. The Error type can also be specified to be SD, SEM, or

None.
5. You can type in a Graph Title, leave it blank, or select the

Kinetica default title.

Graphs in Kinetica
6. The created plot can then be saved to a gallery, by setting the

Write to Saved Gallery option.
by using ‘&’:
Figure 6-28. Example – Inserting Variables into the Group

Label

Graphs in Kinetica
Figure 6-29. Example – Inserting Variables into the Graph

Title
Figure 6-30. Example of Variables Inserted into Group Label

and Graph Title

Graphs in Kinetica
Plotting a Graph You must define the basic attributes for a manual graph before it
can be plotted. This is more time consuming than using the
Manually automated options for a graph display, however, it gives you the
flexibility to easily select the data. You can select a maximum of
three axes. The first axis is always the X-axis. If you choose two
axes, the second axis is the Y-axis. If you choose three axes, the
second axis is Y1 and the third axis is Y3.
Dataset Graph Dialog This dialog is accessed by selecting Select Dataset Graphs from
the View menu. A description of the dialog is provided in the
following table.
Column Description
Datasets Displays a list of all the available datasets in the

study
Column X Displays a list of all the available columns found

across all sample worksheets in the study
Column Y Displays a list of all the available columns found

across all sample worksheets in the study
To plot a scatter graph in log scale with customized titles for two
datasets in a study (example):
1. Launch Kinetica.
2. Click New from the File menu.
3. Enter the following data using the default columns on the

default Plasma worksheet in the Dataset pane:
Note In Kinetica, units always appear in the first cell of

each column. ▲
X Y
h ng/mL

Graphs in Kinetica
X Y
0 0
0.5 04.2356
1 10.2419
1.5 24.0354
2 31.9365
3 37.0409
6 32.4406
9 21.3285
12 15.0597
18 826494
24 2.01253
4. Select Select Dataset Graphs from the View menu. The

Dataset Graph dialog appears; displaying the study datasets
and respective columns (we only have one dataset in this
study).
5. Select Dataset 1, Plasma.X, and Plasma.Y.
6. Click OK. The graph is displayed.
Now try to create a graph with multiple datasets on the same plot
by inserting more data into the study. You can continue
exploring the available editing options by right clicking anywhere
on the graph and selecting Graph Properties.

Graphs in Kinetica
Plotting a Graph There are two ways to plot a graph automatically:

Automatically • Use the graph buttons found on the toolbar
• By inserting a Graph Method.
Graph Buttons The toolbar contains the following buttons for plotting graphs:
Show one graph: Plots the selected column for the current
dataset
Show multiple graphs: Plots the selected columns for all

datasets in the study
These buttons allow you to view different plots very quickly.

They are only activated when you highlight specific columns
found in certain views. There are pre-defined rules the program
uses when a graph is plotted, depending on how many columns
are selected, and the column contents. The rules are explained in
the following table.
Situation Result
Data columns If you highlight an empty column and

empty and select the either Show One Graph or Show
highlighted Multiple Graph buttons on the toolbar, the
graph view displays “Graph Not Available.”
One data If you highlight one column with data, the

column only button activated is the Show One
highlighted Graph button. By default, the plot
generated is a histogram for the current
dataset.

Graphs in Kinetica
Situation Result
Two data If you highlight two columns with data,

columns both graph buttons are activated. By
highlighted default, the plot generated is a scatter plot
with the points joined by a line. If you click
on the Show One Graph button, a plot for
the current dataset only is displayed. If you
click on the Show all graphs button, a plot
for all datasets found in the study is
displayed.
Three data If you highlight three columns with data,

columns only the Show One Graph button is
highlighted activated. By default, an overlay plot is
displayed with a left, bottom and right axis.
This applies to the current dataset only and
the result depends on the data you selected.
You can change the attributes of any graph in the Profile

Properties dialog.

Graphs in Kinetica
Inserting a Graph You can insert a Graph Method so that when you run an analysis,
the graph(s) are automatically displayed. This can be performed
Method in both batch and individual modes.
Kinetica includes several predefined graph methods, which are

Method Graph Plotted
Mean Curve Plot the average of Y versus X and estimates the distribution of the Y value
Mean Curve by Plot the average of Y versus X and estimates the distribution of the Y value.
Group Grouping and sorting are enabled to group individuals based on a
parameter within a graph or to separate them to different graphs based on a
common parameter, respectively.
XY_Graph Plots a graph of selected X and Y columns
XYY_Graph Plots a graph of selected X, Y and Y1 columns as an overlay
X1Y1_X2Y2_Graph Plots a graph of two simultaneous X and Y columns
XYError Graph Plots an error graph using pre-selected X Y columns and the ‘up and down’
Error bars.
Curve Extrapolation Plots a graph showing the slope of the terminal phase of the selected X and
Y columns
To insert a graph method:
1. Select Method from the Insert menu. The Method Selection

dialog appears.

Graphs in Kinetica
Figure 6-31. Insert > Method Menu item
2. Select one of the graph methods from the available list of

hard-coded methods.
3. Enter the input columns under the “User names” column on

the right hand side of the Method dialog. To do so, click in
the corresponding text field to display the drop down menu
as shown in the image below.

Graphs in Kinetica
Figure 6-33. Input Columns Selection
4. Click Insert and click OK to exit the dialog. The graph

method is inserted into the study.
5. Click Calculate one from the Dataset menu on the toolbar or

click the icon to run the analysis. The results are
calculated and displayed in the dataset view. Kinetica will also
automatically display the graph generated by the method in
the Graph Gallery. If you are running in batch mode, a graph
for each dataset is inserted into the Graph Gallery.

Graphs in Kinetica
Figure 6-34. Gallery View
Modifying graph To modify graph attributes:

attributes
1. Right click the graph and select All Properties from the
popup menu. The Profile Properties dialog appears.
Figure 6-35. Profile Properties Dialog
2. Modify the selections, as necessary. You can then apply your

changes to all graphs in the gallery.

Graphs in Kinetica
Modifying Graphs You can modify X and Y axes, ticks, font numbers, spacing,
labels/titles and grid by right-clicking on either graph axis and
selecting “All properties” from the popup menu.
Figure 6-36. All Properties Dialog
The All properties options are described in the following table.
Option Description
Ticks Modify tick length and tick position.
Axis Activate or deactivate the log scale, specify the

minimum, maximum, increment and sub-
ticks.
Numbers Modify font sizes and/or position numbers at

a 45-degree angle.
Space Adjust the distance between the axis and plot,

Between ticks and numbers, numbers and label.
Label Enter a label/name for the selected axis and

adjust the font size.
Note You can modify the title of a graph,

font, and/or alignment by right clicking on
the graph title. ▲

Graphs in Kinetica
Option Description
Grid Modify the background of a plot.
Note A few of the options, including Log scale, Labels and

Tick, can be accessed without using All Properties. Simply right
click on the appropriate axis and select the required item. ▲

Graphs in Kinetica
Displaying Outlier Kinetica has a built-in feature for flagging outlier data. The
program ignores any flagged outlier values found in the dataset
Data and uses an interpolation rule to join the preceding and
succeeding points. Outlier data points are identified in Kinetica
with an exclamation mark (!) before the suspected cell value in
the spreadsheet.
To display outlier data points:
1. Click Open from the Kinetica File menu.
2. Select the Extravascular.kdb file, found in the

Kinetica\data\non compartmental subdirectory.
3. Click OK.
4. Enter an exclamation mark (!) before the C value at time

32.17 hours.
Figure 6-37. Example – Identified Outlier Data Point
5. Press the Enter key.

Graphs in Kinetica
6. Switch to the Dataset Graph view found in the Dataset pane.

Notice the outlier point (the last data point) we specified is
marked.
Figure 6-38. Example – Dataset Graph with Outlier Point Specified
Note The outlier data point is marked with an empty circle

in our example but this symbol can be changed in the Profile
Properties dialog. Notice that the line does not pass through
the outlier point. ▲
7. Run the analysis for this subject. The calculations are

executed and a graph of the terminal phase regression is sent
to the Gallery.

Graphs in Kinetica
Figure 6-39. Example – Terminal Phase Regression Graph
Note Our flagged outlier point remains visible. You can re-
include this point in the analysis by returning to the Dataset
group and deleting the exclamation mark. ▲

Graphs in Kinetica
Displaying Non- Kinetica has a built-in feature for flagging BLQ (below limit of
quantification) data points. BLQ data points are identified in
Detectable Data Kinetica with a less-than sign (<) before the suspected cell value
Points in the spreadsheet. Kinetica does not ignore non-detectable values
found in the dataset when displaying a graph and does not use an
interpolation rule to join the preceding and succeeding points.
Instead Kinetica displays the true line through all points and
highlights the data point with a circle.
To plot a graph with a non-detectable point displayed:

\kinetica\data\non compartmental subdirectory.
3. Click OK.
4. Enter a less-than sign (<) before the last C value which is at

time 32.17 hours.
5. Press the Enter key.
6. Switch to the Dataset Graph view found in the Dataset pane.

Graphs in Kinetica
Figure 6-40. Dataset Graph View
Note The non-detectable data point is marked with an X-

marked circle in our example. This symbol can be changed
using the Profile Properties dialog. If your non-detectable
symbol is different, check the Markers tab in the Profile
Properties dialog. ▲
7. Run the analysis for this subject. The calculations are

executed and a graph of the terminal phase regression is sent
to the Gallery.

Graphs in Kinetica
Figure 6-41. Terminal Phase Regression Graph
Note Our flagged data point remains visible. You can re-
include this point in the analysis by returning to the Dataset pane
and deleting the less-than sign. ▲

Graphs in Kinetica
Mean Curve by Group The graph method plots the average of Y versus X and estimates
the distribution of the Y value. Grouping and sorting are enabled,
Method respectively, to group individuals based on a parameter within a
graph, or to separate them into different graphs based on a
common parameter. The mean curve by group method is
designed to be incorporated into other methodologies as a
template. Global options allow you to set graphical properties to
standardize your graphical reports. To create a graph template:
1. Open the 2WayCrossOver.kdb file, found in the

\kinetica\data subdirectory (include the sample data).
2. Insert the Mean Curve by Group method by clicking on the

insert method icon.
3. Set the method after the available method. Map X to

Extravascular.T and Y to Extravascular.C
Figure 6-42. Method Selection dialog
4. Click Insert then OK.

Graphs in Kinetica
5. Select the Method pane on the left navigation bar and select
the Global Option for Mean Curve by Group.
6. In the Mean Curve by Group dialog, under the Mean Curve

by Group tab, select DrugName for Group variables, Mean
for Mean Type and SD for Error Type. Type “Summary
Statistical Profile” for Graph Title.
Figure 6-43. Mean Curve by Group dialog
7. Select the Graph Properties tab and uncheck the Use Kinetica
Defaults box.
8. Select your preferred symbol, pattern, symbol color, line color

and line size for the first five graphs. Check the Show Error
Bars box. Set both the Symbol size and the Error Bar Size to
4.

Graphs in Kinetica
Figure 6-44. Mean Curve by Group dialog, Graph Properties

tab selected
9. Click OK.
10. Click the Calculate All button, found on the Kinetica toolbar
and examine the mean curve in the gallery.

Graphs in Kinetica
Figure 6-45. Mean curve generated from the mean curve by group method

Graphs in Kinetica
Creating Graph Graph templates offer standardization for the way graphs appear
each time they are plotted. You can create as many graph
Templates templates as you require in Kinetica.
To create a graph template:

\kinetica\data\non compartmental subdirectory (include the
sample data).
2. Click the Calculate All button, found on the Kinetica toolbar

and the Lz plot appears. By default, it is always plotted using
the log scale inside the Graph Gallery.
3. Right-click the X-axis on the Dataset Graph (under Dataset

pane).
4. Deactivate the log scale by deselecting the Log option.
5. Repeat Steps 4 and 5 for the Y-axis.
6. Click OK. The graph is updated.
7. Right-click on the plot and select Save As Graph Template

from the popup menu. The Save As dialog box appears. By
default Kinetica prompts you to save graph templates in the
Kinetica\graph subdirectory with the *.kgr suffix. You can
enter the file name Test.kgr for your template in a different
folder other than the default subdirectory.
8. Click Save.

Graphs in Kinetica
Applying a Custom To apply a custom graph template to another graph of the same
Template to Other Graphs type:
of the Same Type
1. Right click and select Load Graph Template. The Apply
Graph Properties dialog appears.
Figure 6-46. Apply Graph Properties Dialog
2. Select the changes you would like to apply to other graphs

and click OK to exit the dialog.
Note The Save As Graph Template and Load Graph

Template can only be accessed from the Lz plot if the graph is
viewed in its minimum size. Double click to switch between
minimize and maximize view. ▲

Graphs in Kinetica
Applying Graph To apply a graph template:

Templates
1. Select any graph in the Graph gallery.
2. Right click and select Load Graph Template from the popup
menu. The Open dialog appears. By default Kinetica displays
all graph templates present in the Kinetica\graph subdirectory
with the .kgr suffix.
Note This procedure can be accessed only if the graph is

viewed in its minimum size. Double-click to switch from
minimum to maximum view. ▲
3. Select a .kgr template and click Open. Kinetica loads the

template and applies it to the selected graph. The following
message appears: “Apply current properties to all graphs with
the same type?”
Figure 6-47. Apply Template Dialog
• Select Yes. Kinetica applies the styles found within your

template to every graph in the gallery that has the same
type e.g. Scatter.
• Select No. Kinetica applies the styles found within your

template to the selected graph only.

Graphs in Kinetica
Working with the The Kinetica Graph Gallery is a powerful feature for batch graph
viewing, editing and processing. This utility enables you to
Graph Gallery visualize many graphs as thumbnails or a range of different zoom
sizes. Graph properties can be changed on specific plots and
applied to every graph with the same type in the gallery. This
feature enhances productivity and removes tedious graph
management problems.
Gallery Interface Graphs generated automatically during an analysis via methods

are sent to the Gallery by default allowing batch processing of
their graphical properties. Any other graph created manually in
Kinetica or any of the graph views can be sent to the gallery by
right clicking a graph and selecting Send to Gallery from the
popup menu. When graphs are present in the gallery, the view
appears as follows:
Figure 6-48. Graph Presentation in the Gallery

Graphs in Kinetica
Horizontal and Vertical scrollbars allow you to navigate through

the gallery. These scrollbars appear automatically depending on
the number of graphs within the current window size. You can
control graph size by using the Zoom In, Zoom Out, and 100%
Kinetica toolbar buttons. The graphs appear in columns that can
be resized using the mouse.
You can access the Gallery options via a right-click menu. The
options available when the plot viewed is minimized are described
in the following table.
Option Description
Graph Displays the Profile Properties dialog. You

Properties can set graphical attributes, such as:
X-axis: access and adjust the X-axis.
Y-axis: access and adjust the Y-axis.
Profile Properties: Modify a data point

symbol, status and line, AUC and error
bars. Once the Profile Properties dialog box
is open, modifications are applied by
selecting the Common properties check
box. Click Properties to access more
options. After changes are made, a message
appears asking if you want to apply the
same changes to the remaining datasets in a
study.
Show Sets Legend and Show Points Legend:

Display or hide dataset graph legends by
selecting (a check mark should be present)
or deselecting this option.
Maximize/ Maximize the selected graph to fill the

Minimize complete gallery window
Save As Graph Save a graph template for standardizing the

Template way graphs appear each time they are
plotted

Graphs in Kinetica
Option Description
Load Graph Apply a saved template to the current

Template graph. When a template is selected, you are
prompted to apply your selected styles to all
graphs with the same type in the Gallery.
View Selected Highlight a column or selection of graphs

Gallery and creates a separate Gallery.
Number of Specify the number of columns in the

Columns… Gallery
Save Graph As Save the graph in Bitmap (*.bmp), Metafile

(*.wmf) or JPEG (*.jpg) format.
The options available when the plot viewed is maximized are

Option Description
Show sets Show or hide the dataset legend by selecting or

legend deselecting this option.
Show status Show or hide dataset status legend by selecting

legend or deselecting this option.
Add free Enter text information on the graph.

comment
All Modify a data point symbol, status and line,

properties AUC and error bars for a particular dataset or
for all datasets in a study.
Saving a Gallery to File You can save a gallery to a stand-alone file with the .kgg suffix.
1. From Kinetica, open the Group Table.kdb file found in the

Kinetica\example\statistics subdirectory. This file contains the
data for 24 datasets.
2. Click Methods in the Methods pane.

Graphs in Kinetica
3. Locate AUC∗ method.
4. Click Set under the Global Options column. The AUC *

Method Global Options dialog appears.
Figure 6-49. AUC * Method Options Dialog
5. Select the Show Lz Plot check box and click OK. We have
directed Kinetica to plot a graph of the terminal phase
regression for each dataset in the study.
6. Click the Calculate All button on the Kinetica toolbar. A plot

appears inside the Graph Gallery for each dataset in the study.
You now have 24 graphs.
7. Select Save Gallery then To KGG from the File menu. The
Save As dialog appears. By default, Kinetica prompts you to

Graphs in Kinetica
save your gallery in the \kinetica\graph subdirectory with the

*.kgg suffix.
8. Enter the filename Gallery1.kgg and click Save. If the graph is

saved to the current KDB file, you must save the KDB file as
well.
Note This procedure can only be performed if the graph is

viewed in minimum size. Double click to switch between
Saving a Gallery Inside a You can save a gallery inside a Kinetica study (KDB).
KDB File
2. Open the Group Table.kdb file, found in the

Kinetica\example\statistics subdirectory. Notice that the file
contains data for 24 subjects across two treatments (two way
cross-over).
3. Click Methods in the Methods pane.
4. Locate AUC* method.
5. Click Set under the Global Options column. The AUC*


Graphs in Kinetica
Figure 6-50. AUC* Method Global Options Dialog
6. Select the Show Lz Plot checkbox and click OK. We have

directed Kinetica to plot a graph of the terminal phase
regression for each dataset in the study.
7. Click the Calculate All button on the Kinetica toolbar. A plot

appears inside the Graph Gallery for each dataset in the study.
You now have 24 graphs.
8. Select Save Gallery then To Current KDB File from the File
menu. The Save Gallery to Kinetica File dialog appears.

Graphs in Kinetica
Figure 6-51. Save Gallery to Kinetica File Dialog
9. Enter the name My Gallery in the Gallery Name field and

click OK. The gallery and graph is now embedded inside the
Group Table.kdb file.
Note The Gallery list in the Save Gallery to Kinetica File dialog
contains all embedded gallery names. You can save as many
galleries as you like inside a KDB file. If you want to delete a
gallery from a KDB file, select Embedded Objects then Graph
Galleries from the Tools menu. ▲
Opening a Gallery from a Once a gallery has been saved to a stand-alone file with the .kgg
KGG File suffix, it can be re-opened inside Kinetica at a later date.
1. Load Kinetica.
2. Click New from the File menu.
3. Select Open Gallery then From KGG File from the File
menu. The Open dialog appears. By default Kinetica prompts
you to open your gallery from the \kinetica\graph
subdirectory with the .kgg suffix.

Graphs in Kinetica
4. Select a gallery file and click Open.

viewed in minimum size. Double click to switch between
Opening a Gallery from Once a gallery has been embedded inside the active Kinetica
Inside a KDB File study it appears automatically inside the KDB file until it is
deleted at a later date. Simply open a KDB file and switch to the
Gallery pane to see any embedded galleries.
Deleting an Embedded Galleries saved inside Kinetica database files (KDB) can be
Gallery from a KDB File deleted.
1. From Kinetica open the Group Table.kdb file, found in the

Kinetica\example\statistics subdirectory. This file contains the
data for 24 datasets and an embedded gallery file called “My
Gallery” - if you completed the example procedure for saving
a gallery inside a KDB file (see this chapter, section, “Saving a
Gallery Inside a KDB File”).
2. Select Embedded Objects then Graph Galleries from the

Tools menu. The Embedded Galleries dialog appears.
Figure 6-52. Embedded Galleries Dialog
3. Select the gallery called My Gallery from the Gallery List and
click Remove.

Graphs in Kinetica
5. Save the KDB file. The gallery is deleted from the KDB file.

viewed in minimum size. Double-click to switch between
Save Gallery Prompt If you made changes to the Gallery and you did not save them,
when you attempt to exit Kinetica, the Gallery Not Saved dialog
is displayed.
Figure 6-53. Gallery Not Saved dialog
You must select the appropriate option to proceed. The options

are:
• Cancel - cancels the quit operation all together
• Don’t Save Gallery - saves the Gallery and then you will be
prompted to save the KDB file separately from the gallery.
• Save Gallery to file – achieves the same result as choosing

Save Gallery to KGG file from the File menu.
• Save Gallery to KDB – achieves the same result as choosing

Save Gallery to KDB from the File menu.

Graphs in Kinetica
Saving a Graph To save a graph:
1. Select a gallery.
2. Right click and select Save Graph As from the popup menu.
The Save As dialog appears.
3. Enter a path and filename for the graph.
4. Specify one of the following file suffixes:
• BMP = Windows bitmap format
• JPEG = JPEG format
• WMF = Windows metafile format
5. Click Save. The graph is saved in the format that you

selected.

Graphs in Kinetica
Exporting Graphs There are two ways you can export graphs in Kinetica. The basic
method is to simply copy and paste the active graph to the
application of your choice. An advanced option enables you to
export multiple graphs that may be generated in a batch analysis.
Generally, when dealing with large studies, you will want to

export your graphs to a word processor in batch mode without all
the associated statistics generated by the analysis. Kinetica
provides a driver for exporting all graphs created during a batch
analysis. This option is limited to Word 97 and later versions
only, because Microsoft does not support all OLE automation in
previous versions.
To export an active graph file to another application (basic

method):
1. Select a graph by selecting a gallery, a graph or multiple

graphs in a gallery.
2. Select Copy from the Edit menu.
3. Switch to the destination application.
4. Select the Paste command. The graph is displayed.
You can also highlight a graph and select Export to Word or

Export To Excel from the File menu (this executes a copy/paste
operation but sends the graph in metafile format instead of
bitmap). In order to perform this function, you must have
Microsoft Word or Excel defined in the Report Setup dialog
before exporting graphs.
To export batch graphs (advanced method):
1. From within Kinetica, open the Group Table.kdb file, found

in the Kinetica\example\statistics subdirectory. This file
contains the data for 12-subject two-way crossovers study (24
datasets).

Graphs in Kinetica
2. Select Report Setup from the File menu. The Report Setup
dialog appears.
3. Click on Report in the Select Output area of the dialog.
4. Double-click on Graph for Word 97 document in the

Double Click to Set Destination area of the dialog. The Open
dialog appears.
5. You must select a file from this dialog that will be the
destination for your Word output or you can enter a
document name and Kinetica will create a new Word file for
you. For the purposes of this example create a new file called
MyGraphs.doc in the \kinetica\odriver subdirectory (you can
choose a different folder when creating a new file).
6. Click Open to create the file and click OK to exit the Report
Setup dialog. Word 97 Graph export has now been activated.
Note No statistics will be sent to Word when you select this

option. ▲
7. Select Methods in the Methods pane.
8. Locate AUC* method.
9. Click Set under the Global Options column. The AUC*

10. Select the Show Lz Plot check box.
11. Click OK.
12. Click the Calculate all button on the toolbar. The graphs are
exported into the report along with the data, in a tabular
format.

Graphs in Kinetica
Linear Regression Linear regression is a simple test allowing you to analyze linear
regression problems (the relationship between a dependent
random variable and an independent variable) or correlation
problems (the relationship between two random variables).
Kinetica offers you the option to compute the regression using log
or no log transformation of the Y values.
The Linear Regression is calculated using Y = A + B X
where:
A is the intercept
B is the slope.
The correlation coefficient (R), is calculated using the equation
∑ (x −x )( y − y )
i i
R= i
∑ (x −x ) ∑ ( y − y )
2 2
i i
i i
Example of Linear In this example, we have two data columns: X and Y. We will
Regression perform a linear regression analysis on these two data columns
without a log transformation of the Y values.
To complete an analysis for linear regression:
1. Select Open from the Kinetica File menu. The Open dialog
appears. By default, the Data subdirectory is displayed.
2. Select the LinearRegression.kdb file, found in the Program

Files\Kinetica\Example\Statistics directory, and click Open.
3. Select the Study pane. The Study group appears as follows,

containing only the raw data we entered before sending you
the program:

Graphs in Kinetica
Figure 6-54. Study Group – Raw Data Display
4. Select Linear Regression from the Statistics menu. The Linear

Regression dialog appears.
Figure 6-55. Linear Regression Dialog
5. Select X from the X axis Data column list and Y from the Y
axis Data column list. The dialog appears as follows:
Figure 6-56. Populated Linear Regression Dialog

Graphs in Kinetica
6. Click OK to exit the dialog and generate the report.
You can view the results of the Linear Regression in the Study
Info view of the Study pane.

Graphs in Kinetica
Linear Regression To run Linear Regression with CI, see Linear Regression.
with CI The upper and lower interval limit is based on 95% confidence.
The confidence limit is based on the equation:
_
^ 1 (x 0 − x) 2
y( x 0 ) ± t α / 2, n − 2 s +
n S xx
^
Where y is the expected value at x0, t is the t-statistics at
probability level of α/2 and n-2 degrees of freedom, s is the
standard error, Sxx is the corrected sum of squares for the x’s.

Graphs in Kinetica
Mean Curve See the sections, “Mean Curve”, “Plotting Mean Curves without
Statistics”, “Plotting Mean Curves with Statistics”, “Plotting
Statistics Standard or Overlay Mean Curves with Statistics”, and “Plotting
Mean Curves by Group with Statistics” in this chapter.

Graphs in Kinetica
Histogram Statistics The Histogram plot provides information on the evaluation of

parameter distribution frequency. With this plotting, you can
analyze the data and determine which pattern best describes the
data behavior.
For information related to histogram plots for Kinetica

Population Pharmacokinetics, see the section, “Working with
Kinetica Population Graphs” in the chapter, “Population
Pharmacokinetics (PK).”
Histogram Dialog This dialog is accessed by selecting Histogram from the Graph
menu. This dialog is used to define the information to include in
the plot. A description of the items contained in the dialog is
contained in the following table.
Item Description
Data Used to select a parameter or a variable

(derived from the All Variables worksheet).
The distribution of the selected parameter
will be analyzed
Distribution Used to indicate how the specified

Step parameter or variable is displayed on the
plot (width of bar step)
Log If you select this option, the distribution is

Transformation plotted using log transformation
Select Dataset Used to select the datasets to include in the

distribution plot
By Group Used to group the datasets in the

distribution plot by selecting a dataset input
variable
To generate a parameter distribution plot:
1. Launch Kinetica and open the appropriate .kdb file.

Graphs in Kinetica
2. Select the All Variables worksheet in the Study pane and

examine the displayed results.
3. Select Distribution from the Statistics menu. The

Distribution dialog appears.
Figure 6-57. Distribution Dialog
4. Select the parameter or variable for analysis from the Data

list. For example, choose Cmax.
5. Specify the Distribution Step. By default, the distribution

step is 0.5.
6. Specifying datasets to include in the plot
7. Click Select Dataset. The Calculate Range dialog appears.

Graphs in Kinetica
Figure 6-58. Calculate Range Dialog
8. Use your mouse and the CTRL key to select datasets

individually. Click Select All to include all datasets.
9. Click OK to exit the dialog and return to the Distribution

dialog.
10. Select the Log Transformation check box, if required.
Grouping datasets (optional) To group datasets:
1. Select the By Group check box and select the appropriate

dataset input variable from the available list.
2. Click OK to exit the dialog and display the graph.

Graphs in Kinetica
Figure 6-59. Example – Parameter Distribution Probability Curve

Graphs in Kinetica
Scattered XY Plot Scattered XY Plot (Numeric X-Axis) is found under the Graph
menu. Formerly known as Parameter plotting, the scattered XY
(Numeric X-Axis) Plot with numeric X-axis is similar to a scatter plot in order to
Plotting view relationship between different numeric parameters related to
the subject.
To examine the relationship of two parameters:
1. Select Graph | Scattered XY Plot (Numeric X-Axis).
2. Select the numeric parameters for X and Y. To select specific

dataset to perform the analysis, click Select Dataset and
choose the subjects/datasets by CTRL-click. Click OK.
Figure 6-60. X Y Plot Dialog
3. The graph of the relationship is exported to the gallery pane.

Graphs in Kinetica
Scattered XY Plot The scattered XY Plot (Textual X-Axis) is found under the Graph
menu. Formerly known as Categorical plotting, the scattered XY
(Textual X-Axis) plot with textual X-axis provides visualization of categorical
Plotting variable versus numerical variable, as well as paired (spaghetti)
plots related to a particular subject.
To plot categorical parameters against numeric parameters:
1. Select Graph | scattered XY Plot (Textual X-Axis).
2. Select a Categorical (non-numeric) variable for X and a

numeric variable for Y. Click By Pair box and select a unique
identifier, which could be a subject that had undergone
different treatment in X in the drop-down menu. Click OK.
Figure 6-61. Categorical Plot
3. The result is plotted in the gallery as a spaghetti plot.

Graphs in Kinetica
Cmax v s DrugName
5.1
Sbj01
Sbj02
Sbj03
Sbj04
Sbj05
Sbj06
4.8 Sbj07
Sbj08
Sbj09
Sbj10
Sbj11
Sbj12
Cmax()
4.5
4.2
3.9
A B
DrugName
Figure 6-62. Example Graph – Categorical Plotting

7. Methods and Models
This chapter provides information on working with both
methods and models in Kinetica.

Methods and Models
Working with There are two types of method (models) in Kinetica:

Methods and Models • Hard-coded
in Kinetica
• Soft-coded
Equations for both hard-coded and soft-coded methods are

provided in this chapter for your reference. The hard-coded
methods are written in C++. You cannot access the code for these
methods. You can access the corresponding soft-coded methods
that are written in Kinetica Basic (see the Kinetica Basic Reference
Guide for more on Kinetica Basic). You can access and
manipulate the code for these methods.
Note If an output column is left blank, the variable is not

calculated. ▲
The hard-coded methods included in Kinetica are listed in the

following table.
Kinetica Hard-Coded Methods
Adjust Time Curve extrapolation
AUC * Convolution
AUCinter * Deconvolution
AUC Steady State * Derivation
AUC Steady State * Exp (Col)

with Lz
Sparse AUC Linear Regression
Superposition – Linear Regression by Zero

Variable Dosage
Run Macro Log(Col)
Col - Value Macro To Micro

Methods and Models
Kinetica Hard-Coded Methods
Col * Value Micro To Macro
Col / Value Sqrt (Col)
Col + Value T50%
Col a − Col b tN%
Col a * Col b tN% of Cmax
Col a / Col b Value - Col
Col a + Col b X1Y1_X2Y2_Graph
Col Sum XYerror_Graph
Value + Value XYGraph
Value − Value XYYGraph
Value * Value Mean Curve
Value / Value Mean Curve by Group
Value^ Value
Col%
Col^Value
You can also refer to the on-line help system for additional
information.
Units are described by the following hard-coded methods:
• Column units
• Get Column unit
• Set column unit.

Methods and Models
For more information regarding these methods, see the chapter,

“Configuring Units.”
The following hard-coded methods describe compartmental

analysis:
• FitDynamic
• FitMacro0orderinput
• FitMacroExtravascular
• FitMacroIVBolus
• FitMacroIVInf
• FitMicro0orderinput
• FitMicroExtravascular
• FitMicroIVBolus
• FitMicroIVInf
• FitMultiMicroExtravascular
• FitMultiMicroIVBolus
• FitMultiMicroIVInf
• FitMultiMicro
• FitPKPD_Extravascular
• FitPKPD_IVB
• FitPKPD_IVInf
• Micro to Macro
• Macro to Micro
• Simple Hard-Coded Methods

Methods and Models
The following table summarizes Kinetica calculations for most of

the simple hard-coded methods.
Method Kinetica Calculation
Run Macro Runs a specific kdb-appended macro

once
Col + Value Adds a user-defined constant value to

the cell values in the selected column.
Col − Value Subtracts a user-defined constant value

from the cell values in the selected
column.
Col * Value Multiplies a user-defined constant

value with the cell values in the
selected column.
Col/Value Divides the cell values in the selected

column by a user-defined constant
value.
Col a + Col b Adds cell values from two different

selected columns.
Col a − Col b Subtracts cell values from two different

selected columns.
Col a * Col b Multiplies cell values from two

different selected columns.
Col a / Col b Divides cell values from two different

selected columns.
Col Sum Adds all cell values together from the

selected column.
Col % Divides the cell value by a user-

specified value and then multiplies the
result by 100.

Methods and Models
Col ^ Value Raises the cell values in the selected

column to a power of a user-defined
constant value.
exp(Col) Computes the exponent of the cell

values in the column (user-selected).
log(Col) Computes the logarithm of the cell

Sqrt (Col) Computes the square root of the cell

Col Sum Adds all cell values together from the

selected column.
Col % Divides the cell value by your specified

value and then multiplies the result by
100.
Col ^ Value Raises the cell values in the selected

column to a power of a user-defined
constant value.
exp(Col) Computes the exponent of the cell

log(Col) Computes the logarithm of the cell

Sqrt (Col) Computes the square root of the cell

t 50% Computes the time when the cell value

in the column reaches 50% of the final
cumulative values:
t50% = time where Y = Ylast/2
t50% is computed using linear

extrapolation.

Methods and Models
Value − Col Subtracts a user-defined constant value

from the cell values in the specified
column.
Mean Curve Plots mean graph of Y1=f(X1) across

individuals and computes the standard
deviation for the whole group.
Mean Curve by Plots mean graph of Y1=f(X1) across

Group individuals and computes the standard
deviation with the ability to group by
specific parameter.
X1Y1_X2Y2_Graph Plots a graph of Y1 = f(X1) and Y2 =

f(X2).
XYerror_Graph Plots a graph of Y = f(X) with error

bars.
XYGraph Plots a graph of Y = f(X).
XYYGraph Plots a graph of Y = f(X) and a

Y(Overlay) = f(X).

Methods and Models
Area Under the Curve Kinetica’s Area Under the Curve (AUC) calculation methods
include:
(AUC) Calculation
Methods • AUC*
• AUCinter*
• AUCsteady-state*
• AUCsteady-state with Lz*
• Sparse AUC*
The pharmacokinetic parameters computed by these methods are

described in the table below.
Method Column and Variable Outputs
AUC∗ Column Output:
AUC inter* AUC: AUC-ss: compAUC: partial area under the curve
AUC steady state* AUCcum: AUCcum-ss: compAUCcum: accumulated AUC
AUC steady-state* AUMC: AUMC-ss: compAUMC: partial area under the moment curve
with Lz
AUMCcum: AUMCcum-ss: compAUMCcum: accumulated AUMC
Sparse AUC*
R: R-ss: correlation coefficient of linear regression on log transformation
G: G-ss: criteria used to estimate Lz

Methods and Models
Variable Output:
Cmax: maximum concentration
Tmax: time to reach maximum concentration
Tlag: lag time
HVD: Half-value duration. HVD describes the time coverage of drug

concentration in the plasma between half of Cmax and Cmax. This parameter
is estimated as the last time the concentration time curve falls below half-
Cmax subtracted by the first time that it climbs above half-Cmax.
AUClast: AUC from t=0 to tlast (last sampling time)
AUCextra: extrapolated AUC
AUCtot: AUC total (=AUClast+AUCextra)
%AUCextra: percentage of AUC extra with respect to AUC total
Lz
AUMClast: AUMC from t=0 to tlast.
AUMCextra: extrapolated AUMC
AUMCtot: total AUMC (=AUClast+AUMCextra)
AUCall:
If the last sample is at normal, missing or outlier status, AUCall = AUClast
If the last sample is BLQ or zero, or the last several data points are BLQ or
zero, AUCall is calculated as:
AUCall = AUClast + AUCtriangle, where, AUClast is from t=0 to the last

normal status data, and AUCtriangle is:
Clast
AUCtriangle = ( t last +1 − t last )
2

Methods and Models
Clast can be the predicted or observed value, depending on which alternative

has been specified by the user in the method options. tlast+1 is the first BLQ or
zero data sampling time.
There are two outputs from the two options in AUCall calculation:
To use Clast predicted value
To use Clast observed value
R: linear regression coefficient
G: Criteria used for C0 extrapolation and Lz calculation
Rstart: First point used for Lz calculation
Rend: Last point used for Lz calculation
Rnbpoint: Number of points used in Lz calculation
Rsmooth: Ratio between AUC below the curve and AUC above the curve.
The output value is always between 0 and 1. A small difference between AUC
below the curve and AUC above the curve reveals a good estimation of the
real AUC and a good sampling time
Raccurate: Raccurate =1−AUCpartial/AUC, where AUCpartial is the value

that has the largest difference from AUC (AUCpartial was calculated using n-
1 data points.)
C0: Concentration at t=0
T1/2: Half-life of elimination
MRT: Mean residence time
Clearance: Total clearance
Vz: the apparent volume of distribution during the terminal phase
Vss: the apparent volume of the plasma compartment

Methods and Models
ComputedCLast: Last concentration point estimated using the linear

equation obtained from linear regression on log transformed data
Clast(Obs): last observed concentration data.
TLast: Last time point
A: Intercept of the linear equation on log transformed data
B: Slope of the linear equation on log transformed data
R2: Coefficient of determination
AUCinter* AUCi: Total intermediary area under the curve between t start and t end
AUMCi: Total intermediary area under the moment curve between t start
and t end
Cmax: Maximum concentration in the interval
Tmax: Time required to reach Cmax in the interval
Tstart: Enter the time corresponding to the beginning of Tau. If you do not
enter a value, Kinetica uses the time corresponding to the first data point.
Tend: Enter the time corresponding to the end of Tau. If you do not enter a
value, Kinetica uses the time corresponding to the last data point.
AUC steady state* Tau: Dosage interval time (Tau = t end - t start)
Cmax: Maximum steady state drug concentration during a dosing interval
Cmin: Minimum steady state drug concentration during a dosing interval
Tmax: Maximum time corresponding to Cmax
AUCss: Area under the curve during a dosing interval at steady state
AUMCss: Area under the moment curve during a dosing interval at steady
state

Methods and Models
Caverage: Mean or average steady state drug concentration expressed as:
AUCss
Cav =
Tau
%ptf: Peak-through-fluctuation expressed as:
C max − C min
%ptf = 100 ⋅
C average
%AUCdf: Percentage-area-fluctuation expressed as:
AUCabove + AUCbelow
%AUCdf = 100⋅
AUCSS
AUCbetweenC(t)and Cav
= 100⋅
AUCSS
%swing: Degree of fluctuation expressed as:
C max − C min
%swing = 100 ⋅
C min
Tstart: Dosing interval start time
Tend: Dosing interval end time

Methods and Models
AUC steady state* Accumulation: computes accumulation index based on the following
with Lz equation:
1
Rac = where τ is Tstart−Tend
1 − e − Lzτ
CLss: the steady state apparent clearance
Vss: the steady state apparent volume of distribution
Sparse AUC* Composite Tmax: time to reach the maximum average concentration
Composite Cmax: maximum average concentration
SD of Cmax: standard deviation of the maximum average concentration
Composite AUC: area under the average concentration curve
SE of Composite AUC: standard error of the estimate of the area under the
average concentration curve
Approximate df: approximate degree of freedom
Tstart: start time of the sparse area under the curve computation
Tend: end time of the sparse area under the curve computation
Tmax You may specify whether to use the first, last or median Tmax
value. By default, Kinetica uses the smallest value for Tmax for
which C = Cmax. This is applicable in cases where the
concentration curve reaches Cmax several times (during peaks or
plateaus). It is the last value that will indicate the beginning of the
elimination phase.
The soft-coded method CalcAmaxTmax defines the time to reach

the first Cmax as Tmax. You can also enter your own Tmax. If
you indicate a negative Tmax, Kinetica will automatically
calculate a value for Tmax.

Methods and Models
AUC* Options In the subsections below we describe the options available for
AUC* computation.
Mixed log linear The mixed log linear rule is performed in the following way: the
linear rule is applied to the range where concentration is
ascending and the log linear rule is applied to the range where
concentration is descending.
When the concentration increases, the following linear rule is

used:
(C i −1 + C i )
AUCi = ( t i − t i −1 )
2
(t C + t C )
AUMCi = ( t i − t i −1 ) i −1 i −1 i i
2
When the concentration decreases, the log-linear rule is used:
(C i −1 − C i )
AUCi = (t i − t i −1 )
ln(C i −1 / C i )
Log-Linear The log linear rule is used in the following way when the
concentration is descending:
(C i −1 − C i )
AUCi = (t i − t i −1 )
ln(C i −1 / C i )
(t i −1C i −1 − t i C i ) (C i − C i-1 )
AUMCi = (t i − t i −1 ) − (t i − t i −1 ) 2
ln(C i −1 / C i ) ln(C i −1 / C i ) 2
Trapezoidal The trapezoidal (linear rule) is performed in the following way

when concentration is ascending:

Methods and Models
(C i −1 + C i )
AUCi = ( t i − t i −1 )
2
(t C + t C )
AUMCi = ( t i − t i −1 ) i −1 i −1 i i
2
Note When the linear rule is applied to AUC calculation, BLQ,

or zero data points are not included in AUClast (AUC from t=0
to last sampling time) calculation if there are no normal status
data following the BLQ or zero data points. ▲

Methods and Models
BLQ Data You have the option to flag data that are below the limit of
quantization (BLQ). In Kinetica, there are three ways to flag data
as BLQ. These options are described in the following table.
Option Description
Default All concentration values that are BLQ will be

labeled with the original numerical value in
the Dataset spreadsheet. These original values
will be used in all AUC calculations.
Set as 0 All concentration values that are BLQ will be

labeled with the original numerical value in
the Dataset spreadsheet. These original values
will be replaced with “0” for all AUC
calculations.
Set as missing All concentration values that are BLQ will be

labeled with the original value in the Dataset
spreadsheet. These original values will be
omitted from all AUC calculations.
User-defined All concentration values that are BLQ will be

LLOQ labeled with a factor of the entry for LLOQ
column. The options include LLOQ,
LLOQ/2, LLOQ/3 and LLOQ/4.
Note The BLQ option you select will be applied to ALL

undetectable data points in all datasets. ▲
In order to flag data as BLQ, you must first run the analysis, then
identify each undetectable data point with a less-than sign (<)
before selecting a BLQ Data indicator in the AUC Method
Global Options dialog. For more information, see the chapter,
“Working with Graphs,” section “Displaying Non-Detectable
Data Points.”
If you do not specify a BLQ Data indicator, the Default option

will be used for all AUC computations.

Methods and Models
AUC0 Calculation If the first (data) point has a time value of 0, no calculation will
be carried out. In all other cases, Kinetica must know the
concentration value at time 0 to calculate AUC between t0 and t1
(AUC0). The possible options are:
C0 = C1
t 1 C1
AUC 0 = t 1C1 , AUMC 0 = t 1 ⋅
2
This is the default option. It represents a bias on C0 for all

administration routes. It is used when automatic extrapolation
fails.
C0 = 0
C1 tC
AUC 0 = t 1 ⋅ , AUMC 0 = t 1 ⋅ 1 1
2 2
This option is adequate to treat extravascular kinetics and

intravenous infusion.
Extrapolated C0
C 0extra + C1 t C
AUC0 = t 1 ⋅ , AUMC0 = t 1 ⋅ 1 1
2 2
This option permits a correct estimation of the AUC0 for IV

bolus administration. C0 extrapolated is obtained by
extrapolating the concentration profile to t=0 using the linear
regression equation on the logarithmic transformation. This
regression equation is obtained using the first several data points
on the concentration profile. The number of data points to be
included in the calculation is obtained following the same G
criteria (below) as for Lz estimation:
(n − 1)(1 − R 2 )
G = 1−
n−2
where:

Methods and Models
R2= coefficient of determination
n = number of points used to determine Lz
Note Lz is also referred to as Kel or LambdaZ. ▲
AUC Infinity Between the last data point and infinity, the kinetics fall back on
a simple exponential decrease, C = Aexp(−αt), which is a good
approximation when the last samples have been taken sufficiently
“late.”
Kinetica carries out linear regression on the logarithmic

transformation of the last (data) points of the curve. The slope of
this straight line is equal to -Lz (constant rate). In order to
determine the number of (data)points to use in the calculation,
Kinetica attempts the regression with 3, 4, …n points. The best
regression line is the one that maximizes G.
Note AUC Infinity is also called AUCextra. ▲
(n − 1)(1 − R 2 )
G = 1−
n−2
where:
n = number of points used to determine Lz
Note Lz is also referrred to as Kel or LambdaZ. ▲
The options are:
ComputedClast/Lz
The following formula is used:
AUC Infinity = computedClast/Lz, where the estimated value of

the latest data point is used

Methods and Models
Observed Clast/Lz
The following formula is used:
AUC Infinity = observed Clast/Lz, where the observed value of

the latest data point is used.
Note If observation option was selected, AUCinf and

AUMCinf calculation will only use the normal status flag with
data. For example, AUCextra=Clast(observed)/Lz, where
Clast(observed) is a normal status data. ▲
Ci Missing and AUC This option is for handling missing values.

Accumulated
• No interpolation – No value is computed on the line
containing a missing value.
• Interpolation – There is a value computed on the line

containing a missing value.
Note If concentration at ti is missing, called Ci, a linear or log

interpolation for Ci can be selected. ▲
The interpolated Ci is used to calculate AUCi (AUCcum from t=0

to ti can be calculated based on AUCi).
How AUC is calculated in the range of C(i-1) and C(i+1) will

determine whether linear or loglinear interpolation is used.
If Ci is missing and within Ci-1 to Ci+1 , AUC is calculated using

the linear rule, then Ci is interpolated using linear method:
(C i +1 − C i−1 )
C i = C i−1 + (t i − t i−1 )
(t i +1 − t i −1 )
If Ci is missing, and within Ci-1 to Ci+1 AUC is calculated using

the log linear rule, then Ci is interpolated using the log linear
method:

Methods and Models
(lnCi +1 − lnC i −1 )
lnC i = lnC i −1 + (t i − t i −1 )
(t i +1 − t i −1 )
Once Ci is obtained, AUC from i-1 to i and i to i+1 are calculated

using this interpolated value.
AUC Log Start Time By default, Kinetica uses Tmax as the start time to use
logarithmic method to calculate AUC. You can, however, specify
the start time under this option to use logarithmic method to
calculate AUC.
Lz Start Time The default method to select the number of points for Lz
estimation is based on the criteria of G.
(n − 1)(1 − R 2 )
G = 1−
n−2
where:
n = number of points used to calculate Lz
You can also select the starting data point for Lz estimation under
this option. In addition, the calculation of the regression error is
included in the number of points in the termination phase.
Lz End Time This option allows the setting and specification of an “end” data
point for estimating the Lz.
Multiple Cmax The default method for reporting the Cmax value is the to use the
last value. Users can specify if the program should report either
the first or the median value instead.

Methods and Models
Exclude Tmax in Lz This option lets you specify if the Tmax value should be excluded
calculation in the Lz calculations. If this is checked, the program will use all
time points but the Tmax value.
BLQ Before First Non-Zero This option lets you specify if BLQ values before the first non-
Normal Data = 0 zero normal data in the dataset need to be set to zero for the
calculations. By default this option is not checked.
Partial AUC This option allows you to calculate the area between the last
measurable concentration and the following BLQ, depending on
the BLQ option set.
• If BLQ is set as missing, the area will not be calculated.
• If BLQ is set as default, partial AUC will be calculated as the

area between the last measurable concentration and the value
after the < sign.
• If BLQ handling is set as 0, the partial AUC will be the

triangle between the last measurable concentration and 0.
Use outlier in AUC This option lets users specify if all outlying values in the datasets
calculation should be used for the AUC calculations. The default is the
option not checked, i.e. the outliers will be ignored.
C0 Start Time (for IV Bolus administration)
C0 extrapolated is obtained by extrapolating the concentration

profile to t=0 using the linear regression equation on the
logarithmic transformation. The regression equation is obtained
using the first several data points on the concentration profile.
The number of data points to be included in the calculation is
obtained following the same G criteria as for the Lz estimation.

Methods and Models
Show Lz Plot There are two choices for the Show Lz Plot option:
• Yes: Graph appears after running analysis.
• No: Graph does not appear after running analysis.
Special Cases: Missing, You can assign one of three status flags to any data point. In
Outlier, Undetectable and addition, the error flag is output to a spreadsheet cell when the
value for that cell cannot be computed due to an error. The flags
Error Flags
available for selection are listed in the following table:
Status Flag Example
Missing No flag symbol Leave spreadsheet cell

empty
Outlier ! ! 999.99
Undetectable < < 0.0001
Error #ERR #ERR
Note The missing, outlier, or error status given to data points

means that the points will be systematically ignored during
calculations and will therefore have no effect on the results, unless
the use Outliers options is checked, as described above. ▲

Methods and Models
AUCinter* Method The AUCinter* method is identical to the AUC* method except
that it enables you to choose a time interval in which to calculate
the AUC. The result is a partial AUC at this interval.
The pharmacokinetic parameters computed are described in the

following table.
Parameter Kinetica Calculation
AUC Partial area under the curve between t start and

t end
AUCcum Accumulated area under the curve between t

start and t end
AUMC Partial area under the moment curve between t

start and t end
AUMCcum Accumulated area under the moment curve

between t start and t end
AUCi Total intermediary area under the curve

between t start and t end
AUMCi Total intermediary area under the moment

curve between t start and t end
Cmax Maximum concentration in the interval
Tmax Time required to reach Cmax in the interval
Tstart Enter the time corresponding to the beginning

of Tau. If you do not enter a value, Kinetica
uses the time corresponding to the first data
point.
Tend Enter the time corresponding to the end of

Tau. If you do not enter a value, Kinetica uses
the time corresponding to the last data point.

Methods and Models
AUCinter* Options AUCinter* method contains the same set of options as in AUC*
method for computing AUC. For more information, see the
Linear, Log Linear, Mixed Log Linear information in the AUC*
Method section of this chapter.
Mixed log linear The mixed log linear rule is performed in the following way: the
linear rule is applied to the range where concentration is
ascending and the log linear rule is applied to the range where
concentration is descending.
When the concentration increases, the following linear rule is

used:
(C i −1 + C i )
AUCi = ( t i − t i −1 )
2
(t C + t C )
AUMCi = ( t i − t i −1 ) i −1 i −1 i i
2
When the concentration decreases, the log-linear rule is used:
(C i −1 − C i )
AUCi = (t i − t i −1 )
ln(C i −1 / C i )
Log-Linear The log linear rule is performed in the following way when the
concentration is descending:
(C i −1 − C i )
AUCi = (t i − t i −1 )
ln(C i −1 / C i )
(t i −1C i −1 − t i C i ) (C i − C i-1 )
AUMCi = (t i − t i −1 ) − 2
(t i − t i −1 ) 2
ln(C i −1 / C i ) ln(C i −1 / C i )

Methods and Models
Trapezoidal The trapezoidal (linear rule) is performed in the following way

when concentration is ascending:
(C i −1 + C i )
AUCi = ( t i − t i −1 )
2
( t i −1C i −1 + t i C i )
AUMCi = ( t i − t i −1 )
2
Note When the linear rule is applied to AUC calculation, BLQ,

or zero data points are not included in AUClast (AUC from t=0
to last sampling time) calculation if there are no normal status
data following the BLQ or zero data points. ▲
BLQ Data You have the option to flag data that are BLQ (below the limit of
quantization). In Kinetica, there are three ways to flag data as
BLQ. These options are described in the following table.
Option Description
Default All concentration values that are BLQ will be labeled with the original numerical
value in the Dataset spreadsheet. These original values will be used in all AUC
calculations.
Set as 0 All concentration values that are BLQ will be labeled with the original numerical
value in the Dataset spreadsheet. These original values will be replaced with “0”
for all AUC calculations.
Set as missing All concentration values that are BLQ will be labeled with the original value in
the Dataset spreadsheet. These original values will be omitted from all AUC
calculations.
Note The BLQ option you select will be applied to ALL

undetectable data points in all datasets. ▲
In order to flag data as BLQ, you must first run the analysis, then
identify each undetectable data point with a "less than" sign (<)
before selecting a BLQ Data indicator in the AUC Method
Global Option dialog. For more information, see the sections

Methods and Models
titled “Working with Graphs” and “Displaying Non-Detectable

Data Points”.
If you do not specify a BLQ Data indicator, the "Default" option

will be used for all AUC computations, by default.
BLQ before first non-zero This option allows you to specify if BLQ values before the first
normal data = 0 non-zero normal data in the dataset need to be set to zero for the
calculations. By default, this option is not checked.
AUC Accumulated If the concentration within Tstart or Tend is missing, (e.g. at

Tstart, Ci is missing) a linear or log linear interpolation can be
selected. The interpolated concentration is then used to calculate
the AUC at that missing point. The interpolation follows the
same rule as the AUC ∗ method.
If Tstart or Tend is missing then the actual range for AUCinter ∗

will be generated.
Example A time profile ranging from .13333 h to .33333 h. Since the

timepoint for C=204 (last Concentration datapoint) is missing,
then the actual range (.13333 h to .33333 h ) for AUCinter* will
be generated. Please see Example 1 shown here.
Figure 7-1. Example 1

Methods and Models
AUC Log Start Time By default, Kinetica uses Tmax as the start time to use
logarithmic method to calculate AUC. You can, however, specify
the start time under this option to use logarithmic method to
calculate AUC.
T Start The default method to select the number of points for Lz

estimation is based on the criteria of G.
(n − 1)(1 − R 2 )
G = 1−
n−2
where:
n = number of points used to calculate Lz
You can also select the starting data point for Lz estimation under
this option. In addition, the calculation of the regression error is
included in the number of points in the termination phase.
T End This option allows the setting and specification of an “end” data
point for estimating the Lz.
Multiple Cmax The default method for reporting the Cmax value is to use the
last value. Users can specify if the program should report either
the first or the median value instead.
Use Outlier in AUC This option lets users specify if all outlying values in the datasets
Calculation should be used for the AUC calculations. The default is the
option not checked, i.e. the outliers will be ignored.

Methods and Models
AUC Steady State* The AUC Steady State* method enables you to calculate the
AUC during steady state on only one dosage interval time (Tau).
Methods For a given administration, steady-state parameters are different
from single dose parameters. The pharmacokinetic parameters
computed are listed in the following table.
AUC Partial area under the curve between t start and t end
AUCcum Accumulated area under the curve between t start and t end
AUMC Partial area under the moment curve between t start and t end
AUMCcum Accumulated area under the moment curve between t start and t end
Tau Dosage interval time (Tau = t end - t start)
Cmax Maximum steady state drug concentration during a dosing interval
Cmin Minimum steady state drug concentration during a dosing interval
Tmax Maximum time corresponding to Cmax
AUCss Area under the curve during a dosing interval at steady state
AUMCss Area under the moment curve during a dosing interval at steady state
Caverage Mean or average steady state drug concentration expressed as:
AUCss
Tau
%ptf Peak-through-fluctuation expressed as:
C max − C min
%ptf = 100 ⋅
C average

Methods and Models
%AUCdf Percentage-area-fluctuation expressed as:
AUCabove + AUCbelow AUC between C(t) and Caverage

%AUCdf = 100 ⋅ = 100 ⋅
AUCSS AUCSS
%swing Degree of fluctuation expressed as:
C max − C min
%swing = 100 ⋅
C min
Tstart Dosing interval start time
Tend Dosing interval end time
Note The options available for the AUC Steady State* method
and the AUCinter* method are the same. For more information,
see the section “AUCinter* Method” of this chapter. ▲

Methods and Models
Sparse AUC Method The Sparse AUC method allows you to stack repeated data over
various time points, take the average over each time point and
perform non-compartmental analysis on the averaged data. This
method, based on the article published by Nedelman and Jia, is
also known as the Bailer-Satterthwaite’s method.
Refer to the following articles: Nedelman JR, Jia XW. An

Extension of Satterthwaite's Approximation Applied to
Pharmacokinetics. Journal of Biopharmaceutical Statistics 8(2),
317 - 328 (1998). Also see comments by Holder on the method,
appearing in Holder DJ. Comments on Nedelman and Jia's
Extension of Satterthwaite's Approximation Applied to
Pharmacokinetics. J. of Biopharmaceitical Statistics 11(1&2), 75-
79 (2001).
This calculation can be performed for the design that has:
• more than a single subject measured at one time.
• a subject that can be measured at both ti and tj.
The algorithm computes the standard error of the AUC values

and is based on the trapezoidal (or linear) rule from sparse
sampled data. The input variables are sampling times and
individual drug concentration from plasma or tissue.
Note The options for the Sparse AUC* method and the
AUCinter* method are similar. For more information, see the
section “AUCinter* Method” in this chapter. ▲

Methods and Models
Superposition– The superposition–variable dosage method or the overlay

technique allows you to predict concentration data after multiple
Variable Dosage dosing based on single dose data. Using the original time and
Method concentration data, the method utilizes the Curve Extrapolation
method to get a value for the intercept and slope, using the
“stripping” and regression algorithm. The method can either
select the number of points to fit the terminal descending phase
or allow you to select the start and end time of the terminal
regression phase.
The method assumes linearity and proportionality in the data to

allow a proportional increase in the dose, if a different dose is
given at any interval. The method requires four input columns:
X, Y, Admin Time and Admin Dose, and the initial dose as an
input dataset numeric field. The initial dose in the study pane is
assumed to be the original dose for the single dose data. The
AdminTime and AdminDose columns are for predicting the
time-concentration data for multiple dosages.
You need to tell the method the total number of points to

simulate. The method takes the last simulated time point and
divides it by the total number of points minus 1 to increment the
time points from the first time point all the way to the last
simulated time point. Therefore, you will need to provide n+1
points to include zero time point. For example, if you were to
simulate every 0.125 hour interval up to 24 for the independent
variable, then the value for the total number of output data points
will be 24 × 23 + 1 = 193.
The pharmacokinetic parameters computed are described in the

following table.
Variable Explanation
A Y-intercept of the linear equation of log

transformed data.
B Slope of the linear equation on log-transformed

data.
R2 Coefficient of determination.
R Correlation or regression coefficient.

Methods and Models
Variable Explanation
G Criterion used for selecting number of points for

regression.
Rstart First point used for Lz calculation.
Rend Last point used for Lz calculation.
Rnbpoint Number of points used in Lz calculation.
Rsmooth Ratio between AUC below the curve and AUC

above the curve. The output value is always
between 0 and 1. A small difference between AUC
below the curve and AUC above the curve reveals
a good estimation of the real AUC and a good
sampling time.
Raccurate Raccurate =1−AUCpartial/AUC
where:
AUCpartial is the value that has the largest

difference from AUC (AUCpartial was calculated
using n−1 data points).
Thalf Half-life of elimination.
Lz Elimination rate constant derived from the slope

of the linear equation of log-transformed data.

Methods and Models
Superposition – Variable The options available in the superposition–variable dose method

Dosage Options are explained in the following table.
Option Description
Last The time point for the last value of the

Simulated superposition time
Time point
Number of The total number of points to simulate. You

Output Data need to provide n+1 time points and include
Points the zero time point. For example, if you want
to simulate every 0.125 hour interval up to 24
for the independent variable, then the value
for the total number of output data points is
24×23 + 1 = 193.
Interpolation Algorithms available include trapezoidal, log

method linear and mixed log-linear.
C0 Handling See the AUC* method for an explanation of

C0 handling.
Regression Entry will replace the regression start time in

start the stripping algorithm.
Regression Entry will use this value instead of the last

end value in the independent variable column.
BLQ See the AUCinter* method for an explanation

handling of the BLQ handling options.

Methods and Models
Convolution Method The convolution method is a simulation method used to predict

the blood/plasma concentration when a drug is administered
orally. The principle behind this is the following:
No hypothesis for the absorption model (independent-model

method) exists.
Absorption is an input function represented by a series of rapid

Bolus injections over a brief interval.
General Formula In a linear system, the response c to the input value of f is:
c = cδ * f, where f is the input signal and cδ is the unit impulse

response. Convolution is the process to obtain c with known cδ
and f.
In practice, the kinetic profile of the drug by IV is known (TIV

represents IV time; and CIV represents IV concentration).
The desired result is a profile of absorption A(t) or a profile of the

rate of absorption dA/dt. In fact, Tos (time corresponding to the
oral administration) and A(t) or dA/dt are already known.
The purpose for using such a method is to obtain the profile of

the drug (by simulation) if it were given orally, with Cos
(concentration for oral solution) as a byproduct.
The equation used in convolution is:
1 n dA t −t
Cos =
DIV
∑ dt ∫t nn−t ii −1 C IV dt
i =1
where:
Cos = Concentration for oral administration predicted by the

simulation
DIV = IV bolus dose
dA/dt = Rate of absorption

Methods and Models
CIV = Concentration under IV bolus administration
The conditions of use are:
The reference time is the time corresponding to the oral

administration. Before using the convolution method, you might
want to use the “Adjust Time” method. This method computes
the missing values of CIV at time Tos.
At t = 0, A(t) = 0 or dA/dt =0
Convolution Options There are a variety of convolution options.
Interpolation The interpolation option compensates for missing values.
No
No value will be computed on a line containing a missing value.
Yes
A value will be computed on the line containing a missing value

obtained by interpolation.
For more information, see the AUCcum section in the “AUC*

Method” section of this chapter.
AUC Refer to the AUCcum section in the “AUC* Method” section of

this chapter.
C(IV)0 When there is no value entered for t for the C0 estimate option,
C0extrapolated is determined by extrapolating the curve to t=0
obtained through linear regression on the logarithmic
transformation using the first several data points.

Methods and Models
T for C0 Estimate and T for Lz T for Lz estimate allows you to specify a start time for terminal
Estimate slope determination. When there is no value entered for the t for
Lz estimate option, the program estimates a suitable starting
point for Lz calculation by performing these steps:
1. Kinetica attempts the regression with 3, 4, to n points on the

logarithm transformation.
2. Calculate G:
( n − 1)(1 − R 2 )
G = 1−
n−2
where:
R2= coefficient of determination of the regression line on the

logarithmic transformation.
n = number of points used for the regression.
3. The number of points used that resulted in the maximum G

becomes the starting time point for Lz calculation. (Kinetica
starts regression from the last point going backward. For each
timepoint it will compute a G value until it reaches Tmax.
Then the algorithm will use the largest G value as the starting
regression point.)
T for C0 Estimate The T for C0 estimate allows you to specify a start time to execute
the backward extrapolation of the IV profile.
When there is no value entered for t for the C0 estimate option,

C0-extrapolated is determined by extrapolating the curve to t=0
obtained through linear regression on the logarithmic
transformation using the first several data points.
The number of points to include in the calculation is obtained

following the same criteria, G, as used for Lz estimation.

Methods and Models
Deconvolution Deconvolution is the process to obtain f with known c and cδ, or

Method cδ with known c and f. In pharmacokinetics, cδ is the drug
concentration in the plasma (or blood) resulting from an
instantaneous unit input of a drug.
Deconvolution is the reverse process of convolution. General

specifications for deconvolution are explained below.
In a linear system, the response C to the input value of f is:
c = cδf
where:
f is the input signal and cδ is the unit impulse response.
Application of This method is applied to oral doses c = cδf, where cδ is the

Deconvolution blood/plasma concentration resulting from a unit impulse input; f
is the input function. With known cδ and c, f can be estimated
from deconvolution analysis.
Method of Deconvolution This example includes both an IV and an OS (oral solution),

Calculation however the calculation method is the same when it comes to
deconvolution. The data/input values are cδ, IV, as well as the
concentration obtained by an OS.
If f is considered constant for the intervals between t(i-1) and ti

the result is f = fi = constant
d A
Note = f = rate of deconvolution. ▲
d t

Methods and Models
∆ Ai
= fi
∆ ti
1 n ∆Ai
c ostn = ∑
Do i=1 ∆ti
∆AUCiv( tn( −tnt−( iti−)1))
where:
Do: initial dose of IV.
Cos: concentration of oral administration.
AUC: area under the curve.
The time reference is based on the oral administration, by

interpolation (logarithmic). The two time references can be made
to coincide.
∆A1 Cos1
= Do
∆t1 ∆AUC 0t1
and A0 = 0
A1 - A0 = ∆A1
Therefore A1
Then, by using:
n−1
∆Ai
Cosn . Do − ∑ . ∆AUC tntn−− tti( i−1)
∆A n i=1 ∆ti
=
∆t n ∆AUC0tn− t ( n−1)
with

Methods and Models
∆An
A n = A n−1 + .∆tn
∆tn
We obtain the result An for all n, as well as f.
Deconvolution Options There are a variety of options for deconvolution.
No
No value will be computed on the line containing a missing

value.
Yes
A value will be computed on the line containing a missing value

obtained by interpolation.
For more information, see the AUCcum section under the

section, “AUC* Method” of this chapter.
AUC Refer to the section “AUC* Options” of this chapter.
CIV (0)
CIV(0)= user-defined
Extrapolated CIV(t=0)
Note For t for C0 estimate (if needed) and T for Lz estimate (if
needed), see the section, “Convolution Method” of this chapter.
▲

Methods and Models
Derivation Method Computes the derivative.
Example: Input columns: t (time) and A (amount of absorbed

drug)
Output columns: dA/dt (rate of absorption over time)
This method computes the derivative dA/dt from t and A.
Derivation Options There are a variety of derivation options available.
• No: No value will be computed on the line containing a

missing value.
• Yes: A value will be computed on the line containing a

missing value obtained by interpolation.
dA use
An-1 and An+1: the derivation is calculated as follows:
⎛ dA ⎞ A (n +1) − A (n −1)
⎜ ⎟n =
⎝ dt ⎠ t (n +1) − t (n −1)
The derivation of the point at n is calculated by taking the values

of the points at (n-1) and (n+1).
An-1 and An: The derivation is calculated as follows:
⎛ dA ⎞ A ( n ) − A ( n −1)
⎜ ⎟n =
⎝ dt ⎠ t ( n ) − t ( n −1)
The derivation of the point at n is calculated by taking the values

of the points at (n-1) and at (n).
⎛ dA ⎞ Az − Ay
A ± ∆A : ⎜ ⎟n =
⎝ dt ⎠ tz − ty

Methods and Models
with:
ty = tn – ∆
tz = tn + ∆
⎡ A ( n ) − A ( n −1) ⎤
⎢⎣
(
Ay = ⎢ ty − t (n−1) ⋅ ) ⎥ + A ( n −1)
t ( n ) − t ( n −1) ⎥⎦
⎡ A ( n +1) − A( n ) ⎤
⎢⎣
(
Az = ⎢− t (n +1) − tz ⋅ ) ⎥ + A ( n +1)
t ( n +1) − t ( n ) ⎥⎦
Linear Regression Method This method enables you to calculate a linear regression:
Y = a + bX
Where:
Y = Y values
X = X values
a = Intercept
b = Slope
r = Coefficient of correlation.
∑ (xi
i − x )( yi − y )
r=
∑ (x − x) ∑(y − y)
2 2
i i
i i

Methods and Models
Linear Regression by This method enables you to calculate a linear regression through
the origin: Y = b X.
Zero Method
where:
Y = Y values
X = X values
b = slope
This method is used when you want to force a line through the
origin, even in the absence of data at the point of origin.

Methods and Models
Macro to Micro The Macro to Micro method enables you to get micro constants
from fitting methods that produce macro constants. The
Method relationship between macro and micro constants is dependent on
the model.
One-Compartment Models The principles of the one-compartment model are shown in the
diagram below.
Figure 7-2. One compartment model schematic
Kel = Lz = alpha
C0 = A
Two-Compartment The principles of the two-compartment model are shown in the

Models figure below.
Figure 7-3. Two compartment model schematic

Methods and Models
Two-Compartment Micro The two-compartment model uses the following constants:

Constants
C0 = A + B
αβ
K el =
K 21
Aβ + Bα
K 21 =
C0
K12 = α + β - (K21 + Kel)
Three-Compartment The figure below is a schematic of a three-compartment model.

Models
Figure 7-4. Three-compartment model schematic
Three-Compartment Micro The constants for the three-component micro model are:
Constants
C0 = A + B + C
a = α+ β+ γ

Methods and Models
Cα + Bα + Aγ + Bγ + Aβ + Cβ
b=
− Co
Cαβ + Bαγ + Aβγ
c=
Co
−b− ( b2 − 4c)
K 31 =
2
K21 = -b – K31
αβγ
Kel =
K 21K 31
K12 =
(βγ + αβ + αγ − K21a − KelK31 + K221)
(K31 − K21)
K13 = a – (Kel+K12+K21+ K31)

Methods and Models
Micro to Macro The Micro to Macro method enables you to get macro constants
from fitting methods that produce micro constants. There are
Method relationships between micro and macro constants for different
models.
One-Compartment Models Below is a schematic for one-compartment models.
Figure 7-5. Schematic for a one-compartment model.
The constants used in one-compartment models are:
Kel = α
Dose
A = Co =
Vc
Two-Compartment Below is a schematic for two-compartment models.

Models
Figure 7-6. Schematic for a two-compartment model

Methods and Models
The constants for two-compartment models are:
a = Kel + K12 + K21
b= a2 - 4 Kel • K21
1
α = (a + b)
2
β=a–α
Dose
C0 =
Vc
⎛ K −α ⎞
A = C0⎜⎜ 21 ⎟⎟
⎝ β −α ⎠
B = CO - A
Three-Compartment A schematic for three-compartment models is shown below.

Models
Figure 7-7. Schematic for a three-component model

Methods and Models
Three-Compartment Macro The constants for three-compartment models are given below:
Constants
a = Kel + K12 + K21 + K13 + K31
b = Kel • K21 + Kel • K31 + K12 • K31 + K13 • K21 + K21 • K31
c = Kel • K21 • K31
1
aa = a
3
1
bb = aa 2 − b
3
1
cc = aa 3 + ( c − aa ⋅ b)
2
1 bb 3
ϕ = Arc tg −1
3 cc 2
α = aa + 2 bb ⋅ cos ϕ
β = aa + 2 bb ⋅ cos⎛⎜ ϕ + π ⎞⎟
4
⎝ 3 ⎠
γ = aa + 2 bb ⋅ cos⎛⎜ ϕ + π ⎞⎟
2
⎝ 3 ⎠
Dose
C0 =
Vc
(α − K 21 ) ⋅ (α − K 31 )
A = C0 ⋅
(α − β ) ⋅ (α − γ )
(β − K 21 ) ⋅ (β − K 31 )
B = C0 ⋅
(β − α ) ⋅ (β − γ )
C = C0 – B – A

Methods and Models
tN% Method The tN% method enables you to obtain the time corresponding
to N% of a cumulative curve, using a linear extrapolation.
Condition for use: the point corresponding to the tN% has to be

between two values. If this is not the case, Kinetica does not
calculate the value of tN%.
Ylast ⋅ N
tN% = time when Y =
100
N must be between 1 and 99.
tN% Option N must be between 1 and 99.

Methods and Models
tN% of Cmax Method The tN% of Cmax method enables you to obtain the time
corresponding to N% of a maximum point, using a linear
extrapolation. It is used generally to obtain t75% of Cmax in
bioequivalence studies. TN% of Cmax = time where
Cmax ⋅ N
C=
100
N must be between 1 and 99.
tN% of Cmax Option N must be between 1 and 99.

Methods and Models
Kinetica Method Kinetica offers the ability to quickly and easily generate methods
for non-population methods. The interface for writing these
Editor methods is called Kinetica Method Editor, located in the
Methods pane. You are not obliged to use this editor to create
your methods, any text editor will do, but you must use it to
compile the methods for use in Kinetica. The methods and
models must be written in a VBA-like language (Visual Basic for
Applications). We call this language Kinetica Basic.
For more information related to Kinetica Basic, see the Kinetica

Basic Reference Guide.

Methods and Models
Opening All methods and models in Kinetica are stored in ASCII files with
the .BAS suffix.
Methods/Models
To open a method/model:
1. Select the Methods pane.
2. Click on Method Editor.
3. Select Open from the File menu. The Open dialog appears.
4. Select the .BAS file containing the appropriate method or

model and click Open.
Compiling To compile a method/model:

Methods/Models
1. Select the Methods pane and click on Method Editor.
2. Open the appropriate method or model and make changes, if

required.
3. Select Method Editor then Compile from the Tools menu.

Kinetica executes a syntax check. Any errors found will be
directed to a message box; otherwise the non-population
method/model will be compiled.
Note Errors found during the compilation process will only

be displayed in a message box if this was specified in the
Report Setup dialog. ▲

Methods and Models
Saving Changes All methods and models in Kinetica are saved in ASCII files with
the .BAS suffix.
2. Click on Method Editor.
4. Select the .BAS file containing the appropriate method or

model and click Open.
5. Make the required changes.
6. Select Save or Save As from the File menu.
Copying and Pasting To copy and paste information:

Information
2. Open the appropriate method or model.
3. Copy by dragging the cursor over the information you want

to select.
4. Press and hold down the Ctrl key and then press the C key.
5. Click at the location where you want to paste the

information.
6. Press and hold down the Ctrl key and then press the V key.

Methods and Models
Deleting Information To delete information:
2. Open the appropriate method or model.
3. Drag the cursor over the information you want to delete.
• Press the Delete key
• Press the Backspace key

Methods and Models
Kinetica Designer We use the concept of “symbolic modeling” to explain how we

generate our differential equations. This means that we will create
a symbolic representation of our model before generating the
interpreted code for compilation in the main program. The
Kinetica Designer enables you to save your symbolic model so
that you can re-open it at a later date. The file format of the
symbolic model is “private.” If you want to include the symbolic
model in a report, you must select Copy from the Edit menu to
transport it between the clipboard and the destination application
(e.g. Word or Excel). When pasted into a different application,
the symbolic model will be imported as a picture in the Windows
Metafile Format (for additional information related to metafiles,
refer to your Windows documentation).

Methods and Models
Designer Dialog This dialog is accessed by selecting Designer, then Standard from
the Tools menu.
Figure 7-8. Designer Dialog
Menu Bar The menu bar at the top of the Designer screen has three pull-
down menus: File, Edit and Help.
File Menu The File menu offers six options for manipulating existing
models, or models you will create. These options are described in
Item Description
New Create a new symbolic model. You will be

prompted to save any currently existing
symbolic model that has not already been
saved.
Open Open an existing symbolic model
Save Save the current symbolic model
Save as Rename and save the current symbolic

model under a different file name

Methods and Models
Item Description
Make Kinetica Generate the interpreted source code

Basic file necessary to compile the current symbolic
model for use in an analysis
Exit Close Designer and return to the

Interpreter. You will be prompted to save
any currently existing symbolic model that
has not already been saved.
Edit Menu The Edit menu offers two options for manipulating existing
models, or models you will create.
Item Description
Copy Copy the current symbolic model (current contents

of the Designer window) to the Windows clipboard
facility.
Paste Paste the contents of the clipboard into the Designer

window. This event is only available when the
contents of the clipboard facility are in the private
format recognized by Designer.
Help Menu This menu displays help information for the current version of
designer.
Toolbar The toolbar offers a series of nine icons. When you select icons,
you can position the respective objects in the window in order to
create your symbolic model. You can also use the available text
box to enter a name for a new model.

Methods and Models
Figure 7-9. Kinetica Designer Toolbar
The table below describes the different elements of the Kinetica

Designer toolbar.
Item Description
Select Enables normal mouse and menu

operations.
Add Adds a compartment to the symbolic

Compartment model. Each compartment added is
assigned a sequential number. The
maximum number of compartments
allowed is nine. If you delete a
compartment, the remaining compartments
are automatically re-numbered in sequential
order. The compartment number appears in
the center of the compartment symbol.
The following symbol represents each

compartment in your symbolic model and
is sequentially numbered:

Methods and Models
Item Description
Add Link Add a link to the symbolic model. There are

two types of link icons available from the
tool bar:
First order link
Michaelis-Menten.
Additionally, each link can appear

differently in your symbolic model
depending on where you place it (for more
information, see the section, “Link Types”
of this chapter). The following symbols
represent the four different appearances of
possible links in your symbolic model:
Define Admin IV BOLUS. Add an intravenous bolus

administration. The following symbol
represents an intravenous bolus
administration in your symbolic model:
IV INFUSION. Add an intravenous

infusion administration. The following
symbol represents an intravenous infusion
administration in your symbolic model:

Methods and Models
Item Description
EXTRAVASCULAR. Add an extravascular

administration. The following symbol
represents an extravascular administration
in your symbolic model:
Note: You can only specify one

administration type per symbolic model.
Add Output Add an output (elimination) object to the

symbolic model. You can specify any
number of outputs, but can only assign one
output per compartment. The following
symbol represents an output in your
symbolic model:
Specify Sample The sample number appears in the center of

the symbol. The following symbol
represents a sample (observed
compartment) in your symbolic model:
Model Name Enter the name of a new model in this field

Methods and Models
Link Types There are two types of link:
• First Order rate
E max C
• Michaelis-Menten: E = E 0 ±
EC 50 + C
Each link has a unique appearance. The appearance of the links in

your symbolic model depends on the context.
Link between You can link two compartments with a First Order link or a
Compartments Michaelis-Menten link. The links can go in both directions. They
appear as follows:
First Order Link Michaelis-Menten Link
Figure 7-10. Schematic of compartment links.
Link between IV Bolus, IV This type of link can only be added between an administration
Infusion or Extravascular symbol and a compartment. The link can only go in one
direction: from the administration symbol to the compartment.
Administration and
The two link types have the following appearance:
Compartment
Figure 7-11. Administration-compartment links

Methods and Models
Link between You can only link a compartment and a sample with a First
Compartment and Sample Order link. The Michaelis-Menten link can not be used. The link
can only go in one direction, from the sample to the
compartment.
The link appears as follows:
Figure 7-12. Compartment-Sample link
Link between You can link a compartment and an output using either a First
Compartment and Output Order link or a Michaelis-Menten link but the link can only go
from the compartment to the output.
The link appears as follows:
Figure 7-13. Compartment-Output link

Methods and Models
Available Tool You can perform various operations using the mouse, in
conjunction with the available tools.
Operations
Adding Compartments, To add compartments:

Administrations, Samples
and Output 1. Select the object you want to add to your model from the
toolbar.
2. Select the window area. The corresponding object appears

where you clicked in the window.
Note Once you have clicked in the window area, the

program automatically moves focus to the Select tool in
preparation for your next selection or normal menu and
mouse operation. ▲
To add samples:
1. Select the Sample item from the toolbar.
2. Select the window area. The Associate Sample dialog appears.
Figure 7-14. Associate Sample Dialog
3. Enter the sample number and sample name. The name you
enter as the sample name must correspond to the name of the
sample worksheet in the Dataset workbook containing the
relevant sample data.
4. Click OK to confirm your selections and exit the dialog.

Methods and Models
Note If you select Cancel, the sample object is still added to

the symbolic model because you are only canceling the
Associate Sample dialog. If you do not want the sample object
just created, select the object and select the Delete or
Backspace key on the keyboard. ▲
Deleting Compartments, To delete compartments, administrations, samples or output:

or Output 1. Select the object you want to delete from your model.
2. Select the Delete or Backspace key. The object is deleted,

including any associated links.
When you select an object, its border changes from a solid to a

dotted line, allowing you to confirm that you are selecting the
correct object.
Figure 7-15. Border outline changes when object is selected.
Changing the Symbolic Kinetica Designer is very flexible and lets you easily make changes
Representation of a to your symbolic model. You can make the changes and additions
Model at any time.

Methods and Models
Changing Sample Names Changing the sample number is particularly useful if you deleted
and Numbering samples that were initially placed sequentially within your
symbolic model. Changing the sample number enables you to
reorder the samples.
Note You can not assign a sample number that currently exists
but you can specify an existing sample name. ▲
To change the sample name and number:
1. Double-click the sample icon in the symbolic model. The

Associate Sample dialog appears.
2. Enter the sample number and name.
3. Click OK to save the information and exit the dialog.
Moving Compartments, To move compartments, administrations, samples and output:

and Output 1. Select the object you want to move.
2. Drag it to another location while holding down the mouse

button. The object follows the mouse movement, enabling
you to visualize the object in relation to the model and its
new destination.
3. When you reach the new destination, release the mouse

button. The object remains at this position.
Note While dragging the object, any associated links also move.
This enables you to re-visualize the entire model in relation to the
object positions. ▲

Methods and Models
Creating and Deleting Follow the instructions below for creating and deleting links.
Links
Creating Links To create links:
1. Select the appropriate type of link by clicking on one of the

link icons from the toolbar.
Michaelis-Menten Link First Order Link
Figure 7-16. Link types
2. Select the object in the window that will be the link origin
(i.e. an administration).
3. While continuing to hold down the mouse button, drag the

arrow to the link destination (i.e. a compartment).
4. The link arrow appears. Its appearance will depend on the

link you selected from the toolbar. The arrowhead always
points towards the link destination.
Figure 7-17. New link created

Methods and Models
Deleting Links To delete links:
1. Select the specific link you want to delete.
2. Select the Delete or Backspace key and the link disappears.
3. While continuing to hold down the mouse button, drag the

arrow to the link destination (i.e. a compartment).
4. The link arrow appears. Its appearance depends on the link

you selected from the toolbar. The arrowhead will always
point towards the link destination.
Note When you select a link, it changes from a solid to a dotted

line, enabling you to verify that you are deleting the correct link.
▲
Figure 7-18. Selected link path shows a dotted line

Methods and Models
Example of a An example of a method created graphically using the Kinetica

Designer appears in the following figure. The Kinetica basic code
Designer Method compiled from this method is described in this chapter.
Figure 7-19. Method Graphically Created using Kinetica

Designer

Methods and Models
Using Designer to If you want to use your symbolic model in a Kinetica analysis,
you need to generate the corresponding Kinetica Basic code.
Generate a (Refer to the Kinetica Basic Reference Guide for more on Kinetica
Differential Equation Basic.)
Generating Kinetica To create a Kinetica Basic file:

Basic Code
1. Create the symbolic representation of your model (see the
sections, “Designer Dialog” and “Available Tool Operations”
in this chapter).
2. Select Make Kinetica Basic File from the File menu. The Save
As dialog appears.
3. Select the file path where you want to save the basic file and
enter a file name.
Note You must save the file with a .bas suffix or Kinetica
will not be able to open the file. We recommend that you
save Kinetica Basic files in the \Kinetica\Models sub-directory
because this folder opens by default when you open a Kinetica
Basic file. ▲
4. Click Save to create the basic file and exit the Save As dialog.
The following message appears: “Do you want to save the
changes?” Click Yes to save the visual image and close
Designer.
Opening the .bas file To open the .bas file:
1. Click on Method Editor in the Methods pane.
2. Select Open from the File menu and select the new basic file.
The basic code corresponding to the differential system you
created in Kinetica Designer appears. You can now edit the

Methods and Models
code or compile and run the method. For more information

see the section, Compiling Methods/Models.
An example of a Kinetica basic file originally created using

Kinetica Designer is shown below:
'Interactive model
'Differential system model generated by KinDiff
' time for observations
Dim X as InputColumn
' PLASMA observations
Dim Y1 as ColumnToFit
' PLASMA predicted values
Dim Y1calc as ComputedColumn
Dim Dose as InputNumber
Dim V as Parameter
Dim k10 as Parameter
Dim Z1 as Double
Dim DZ1 as Double
SUB Fit_Interactive_model ()
Dim i as Integer
Dim ret as Integer
Dim hmod as long
hmod = NewInteg("Deriv")
ret = DeclareComp(hmod, Z1, DZ1)
Z1 = Dose/V
For i=1 To X_count ' For each time
If X_status(i)=0 Then ' Check time status and if OK
ret = IntegTo(hmod, X(i)) ' Compute new comp values
If Y1_status(i)=0 Then ' If there is an observation
Y1calc(i) = Z1 ' Get corresponding computed value
Y1calc_status(i) = 0 ' code for Normal value
Else
Y1calc_status(i) = 3 ' code for Missing value
End if
End if
Next i
Y1calc_unit = Y1_unit ' Set units for computed column
End Sub
Sub Deriv (Byval t as double)

DZ1 = -Z1*k10
End Sub

8. Non-Compartmental
Analysis
This chapter describes the numerous Non-Compartmental
Analysis (NCA) templates that are provided with Kinetica.

Non-Compartmental Analysis
Performing Non- The purpose of non-compartmental analysis (NCA) is to provide

an estimate of the kinetic parameters of a drug based on statistical
Compartmental moment theory such as AUC (zero moment), MRT (first
Analysis in Kinetica moment), etc. The methods associated with non-compartmental
analysis algorithms in Kinetica include the following:
• AUC* – all-inclusive first-dose NCA for all types of dosing

administration.
• AUC inter* – partial area under the curve computation; this

method is often associated with other AUC methods within a
template.
• AUC Steady State* – multiple-dose NCA to evaluate

exposure over a specified dosing interval.
• AUC Steady State* with Lz – all-inclusive steady-state NCA

for all types of dosing administrations for a typical steady-
state dosing interval.
• Sparse AUC – sparse sampling NCA based on the Bailer-

Satterwaithe algorithm.
• Non-parametric superposition – simulation of multiple

dosing regimens without assumption of any compartmental
models.

The AUC* Method This section discusses the AUC* method and how it can be
applied to any type of first-dose administration. This method is
the all-inclusive first-dose non-compartmental analysis
methodology that encompasses all routes of administration. One
way of performing non-compartmental analysis is by applying the
AUC* method to the time-concentration data.
Follow the steps below to use the AUC* method.
1. Import time-concentration data.
2. Insert a dataset numeric field called Dose.
3. Click Insert Method and select AUC*.
Figure 8-1. Method Selection dialog
4. Map the Input columns and variables for X, Y and Dose. The
method will perform an auto-map by matching the variable
names. If the variable name is not identical, you need to map
the fields manually by moving the cursor close to the right
hand side of the white space. Click the area to make the
drop-down menu available for selection.
5. Make changes to the output columns and variables, if you

wish.

6. Click insert then OK.
7. Now that you have successfully inserted the AUC* method,

select the Method pane in the left navigation bar.
8. Click the Set button of the AUC* method under the Global
Options (see figure below).
Figure 8-2. Setting Global Options in the Methods pane
9. The AUC* Method Global Options dialog box allows you to

set the computation settings for the NCA. The Unit tab
allows you to set the input and output parameter units.

Figure 8-3. AUC* Method Global Options dialog
10. Once the data are set up, you may perform the
noncompartmental analysis by clicking the double-head icon
. Computation results and terminal phase elimination
graphs will be produced in the Dataset variable and gallery,
respectively.

AUC Computation The AUC from time zero to the last quantifiable measurement
can be estimated using the trapezoidal rule (linear rule), log-linear
and mixed log linear rules. AUMC calculation follows the same
rules as AUC (AUMC is the statistical moment curve where the
segmental AUC is multiplied by the time increment).
• Trapezoidal: computes all values in a linear manner.
• Log linear: computes all values prior to Cmax in a linear

manner and transforms all values after Cmax to log in its
computation.
• Mixed log linear: the computation method where all

ascending phases are computed in a linear manner and all
descending phases are computed based on their log values.
AUC0 Calculation The AUC from 0 to the first sampling time called AUC0 can be
estimated using the following options: C0=0, C0=C1,
Extrapolated C0 and no AUC0 computation. The AUC0
calculation is based on the first cell of the Y column when the
corresponding X column cell is 0. This computation determines
the value for the Y column when the independent variable is 0,
and consequently determines whether the route of administration
is IV bolus or extravascular. The options available are:
• c0 = c1: applies to IV Bolus, where the concentration at the

zero-time point assumes the same concentration for the first
sample collection.
• c0 = 0: assumes that the drug concentration at the zero-time

point is zero. This condition applies to the IV Infusion and
Extravascular routes of administration.
• Extrapolated C0: applies to IV Bolus, where the

concentration at the zero-time point is extrapolated based on
the log values of the first three data collected.
• No AUC0 computation: assumes no computation of the area

under the curve between the zero time point and the first
collected time point.

AUC Infinity The AUC from the last quantifiable measurement to infinity is
called AUCextra and can be estimated using the following
options: Computed Clast/Lz, Observed Clast/Lz, and no AUCinf
calculation. Lz is the slope of the terminal phase using a log scale.
• Computed Clast/Lz: the extrapolated area beyond the last

concentration, based on the estimated last concentration
obtained from the regression divided by the slope of the
regression line.
• Observed Clast/Lz: the extrapolated area beyond the last

concentration, based on the observed last concentration
divided by the slope of the regression line.
• No AUCinf computation: AUC from zero to infinity is not

computed at all.
AUC Cumulated Ci missing and AUCcum (AUC accumulated) can be estimated

using the options Interpolation and No interpolation.
Interpolation applies to cases where there are missing data;
Kinetica allows you to use linear interpolation (between two
points) to estimate the missing value.
Start and End Times The following AUC* method options enable manual entry of
values: AUC Log Start Time, C0 Start Time and Lz Start Time.
• AUC Log Start Time: entry overrides Tmax for the start of
log AUC computation when AUC computation selected is
log-linear. Entry should be a time point in the X column.
• Lz Start Time: entry is used as the start of terminal phase

regression and will override the optimization method based
on the greatest G-value for the selection of start of terminal
regression.
• Lz End Time: entry is used as the end of terminal phase

regression.
• C0 Start Time: entry is used as the starting time for the

backward regression to the time=0 point for IV bolus

administration. By default, three time points are used in the

extrapolation to determine the initial concentration.
BLQ handling The BLQ Data option provides different ways of handling below
the limit of quantification data.
• Default: Data with “<” and assumes the value proceeding the
less than symbol.
• Set as 0: Data with “<” will assume the value of 0.
• Set as missing: Data with “<” will be treated as missing.
• Box for BLQ before first non-zero normal data = 0, if

checked, will treat all BLQ values before the first non-zero
data as 0.
• User-defined LLOQ (lower limit of quantification), if

checked, will override the BLQ data option and enable user
to map the column for the LLOQ values and set BLQ to
LLOQ, LLOQ/2, LLOQ/3 and LLOQ/4.
Infusion Box The infusion check box, if checked, allows you to set the infusion
duration time or map to a dataset numeric variable for the
infusion duration. Note that you need to enter values in the
same unit as the time unit. Select the Inf Value radio button if
you wish to enter a value manually or select Inf Var Name if you
wish to map to a specific field.
Other Check Boxes The remaining check boxes available in the AUC* Method
Global Options window are described below.
Exclude Tmax in Lz calculation If the most optimized G-value lies at the Tmax for the start of
terminal phase regression, the next time point with the most
optimized G value following Tmax will be used instead, if the
box is checked.

Compute Last AUC triangle If the last value is BLQ, with Compute Last AUC Triangle
checked, AUClast will include the AUC of the last triangle if the
value following the last normal data is flagged as BLQ. Note that
AUCall(Obs) always include the last triangle area if the value
following the last normal data is flagged as BLQ.
Use outliers in AUC calculation If checked, any cell marked as an outlier will be included in the
computation of AUC but not used in the terminal phase
regression.
Show Lz Plot If checked, the individual profile with the estimated terminal
phase regression line will be plotted in the gallery view every time
AUC* is run. This box is checked by default.
Multiple Tmax If there is more than one largest concentration value, you may use
the first or last Cmax to report Tmax, or use a median Tmax
value.

Built-in templates for Kinetica provides a number of Non-Compartmental Analysis

(NCA) templates to be used as examples and as working
NCA templates for your analyses. You may follow the instructions for
each NCA template or the NCA Assistant using the AUC*
method.
Three routes of administration are considered; they are

represented by templates named for their route:
• IV Bolus
• IV Infusion
• Extravascular.
In addition, the non-compartmental analysis templates enable

you to perform unit conversion for the following methods:
AUC*, AUCinter* and AUC Steady State*. To use this feature,
you need to specify the input units and select the types of units
you want for the output variables. The unit management feature
will then convert the units to your specifications for the final
output variables. For more information, see the sections, “Unit
Management for AUC*,” “AUCinter*,” or “AUC Steady State*
Methods” in the chapter, “Working with Methods and Models.”

IV Bolus Template The functionality of the IV Bolus template is described in the

subsections below.
Template Inputs and Inputs are numeric fields and columns where you must enter data
Outputs so that Kinetica can successfully complete the analysis. Outputs
are numeric fields and columns where Kinetica displays the
results of the computation. The following input and output
information can be found in the Study Info worksheet in the
Study pane.
Data input (user-entered dataset numeric field values):
Dose – Amount of drug in the galenic formulation
Data input (user-entered dataset column values):
• T – Time
• C – Concentration
Methods The Set Column Unit and Make ConcUnit methods are used to
add units to the columns and assure that Kinetica understands
and inserts the correct final measurement units.
Column Output Variable Output
AUC: partial area under AUClast: AUC from t=0 to tlast (last sampling time)
the curve
AUCcum: accumulated AUCextra: extrapolated AUC

AUC
AUMC: partial area under AUCtot: AUC total (=AUClast+AUCextra)

the moment curve
AUMCcum: accumulated %AUCextra: percentage of AUC extra with respect to AUC total
AUMC

R: correlation coefficient AUMClast: AUMC from t=0 to tlast.

of linear regression on log
transformation
G: criteria used to AUMCextra: extrapolated AUMC

estimate Lz
HVD: Half-value duration is the period at which the drug

concentration is above half Cmax value
G: Criteria used for C0 extrapolation and Lz calculation.
Rsmooth: Ratio between AUC below the curve and AUC above the
curve. The output value is always between 0 and 1. A small difference
between AUC below the curve and AUC above the curve reveals a
good estimation of the real AUC and a good sampling time.
Raccurate: Raccurate =1-AUCpartial/AUC
where:
AUCpartial is the value that has the largest difference from AUC
(AUCpartial was calculated using n-1 data points.)

Computed CLast: Last concentration point estimated using the linear

equation obtained from linear regression on log- transformed data
TLast: Last time point
B: Slope of the linear equation on log-transformed data
AUCall: If the last sample is at normal status, missing and outlier then,
AUCall=AUClast
If the last sample is BLQ or zero, or the last several data points are
BLQ or zero, AUCall is calculated as:
AUCall=AUClast+AUCtriangle,
where:
AUClast is from t=0 to the last normal status data
AUCtriangle is:
Clast
AUCtriangle = (t last +1 − t last )
2
Clast can be predicted or observed value. tlast+1 is the first BLQ or

Zero data sampling time. There are two outputs from two options in
AUCall calculation:
to use Clast predicted value, AUCall(CPred)
to use Clast observed value, AUCall(CObs)

Equations The equations used in the methods are listed below.
T1/2 = ln2/k
AUMC
MRT =
AUC
Dose
Clearance: AUCtot
Dose
Vz: AUCtot. ⋅ Lz
Dose ⋅ MRT
Vss: AUCtot
Viewing an Example of The following example contains data for one dataset. Forty mg of
NCA - IV Bolus Template a drug was administered by IV Bolus. The concentration-time
course was sampled from the plasma and expressed in mg/L and h
respectively.
To view an IVBolus template:
1. Load Kinetica.
2. Select New from the File menu. The New Analysis dialog
appears.

Figure 8-4. New Analysis Dialog
3. Select the IVBolus analysis found on the Non

Compartmental tab.
4. Select the Open with Data check box.
5. Click OK.
Note For this example we entered some data into the

relevant template and saved it as a .kdb file. If you open the
corresponding file in the template subdirectory, you will see
no data. It is ready for your experimental data. ▲
The dataset appears as follows, containing only the raw data:

Figure 8-5. Example Dataset
Before running the analysis, look at a graph of the time versus

concentration values to help decide how to set AUC0:
6. Select the T and Civ columns.
7. Select the Dataset Graph button found on the Dataset pane.

The following graph appears:

Figure 8-6. Example – Dataset Graph Display
9. In the Methods column, select AUC*.
10. Click Set in the corresponding Global Options column. The

AUC* Method Global Options dialog appears.
11. Modify your selections by adjusting AUC and units options.
12. Select the Dataset pane and click the Calculate One button to
run the analysis. The results are displayed.
The Lz plot is displayed automatically when the check box is

selected. Deselect the check box if you do not want to display the
Lz plot.

Figure 8-7. Example – Calculation Results
Note If you have multiple datasets to analyze, you can select

Calculate All from the Dataset menu. The results for all datasets
are calculated in batch mode and displayed using the gallery
feature. You can then make universal changes to the appearance
of your graphs. ▲
You can continue to review the data with the graphical tools:
1. Select the T, Civ and AUCcum columns.
Note To select columns that are non-adjacent, hold down

Ctrl while selecting the non-contiguous column(s). ▲
2. Click the Show One Graph button. The following graph

appears:

Figure 8-8. Example – Single Graph Display
Modifying AUC* Options Some methods contain options you can modify. In this template,
you can only modify the AUC* method.
To modify options for the AUC* method:
1. Select Methods in the Kinetica Methods pane and select

AUC* in the Methods column.


Figure 8-9. AUC* Method Global Options Dialog
3. Specify the following from the Options tab:
Field Name Value(s)
AUC Computation Select mixed log-linear, log-linear, or trapezoidal
AUC0 Calculation Select an initial phase extrapolation option: C0=C1, C0=0,

Extrapolated C0, or no AUC0 computation
AUC Infinity Select a terminal phase extrapolation option: Computed Clast/Lz,

Observed Clast/Lz, or no AUCinf computation
AUC Cumulated Select No Interpolation or Interpolation. Use an interpolation rule

when missing values are found.

Field Name Value(s)
AUC Log Start Time Enter a start time for AUC log calculations if you want to override the
values previously generated by Kinetica
Lz Start Time Enter a start time for Lz calculations if you want to override the values
previously generated by Kinetica.
Lz End Time Enter the last timepoint for the Lz regression calculation.
C0 Start Time Enter a start time for C0 calculations if you want to override the values
previously generated by Kinetica.
Show Lz Plot Select the check box to simultaneously plot both the fitted terminal
phase and experimental points. Deselect the check box if you do not
want to display the Lz graph.
Exclude Tmax in Lz Select the check box to exclude Tmax from the estimation of the
calculation terminal slope.
BLQ Data Select Default, Set as 0, or Set as missing. For more information, see the
section, “AUC* Options” in the chapter, “Working with Methods and
Models”.
The default will take whatever the LQ value (e.g. <0.2 will be calculated
as 0.2).
Set as 0 will calculate all BLQ data as 0.
Set as missing will skip the BLQ data and will not use the BLQ in the
calculation.
User-defined LLOQ will set all BLQ data as a factor of the entry for
LLOQ column. The options include LLOQ, LLOQ/2, LLOQ/3 and
LLOQ/4.
Note In order to flag data as BLQ, identify each undetectable data

point with a “less than” sign (<) before the data. For more information,
see the section, “Displaying Non-Detectable Data Points” in the
chapter, “Working with Graphs.” ▲

Field Name Value(s)
BLQ before first non- Select the check box to treat all BLQ before the first quantifiable data as
zero normal data = 0 0.
Use Outliers in AUC When enabled, marked outliers are used in the AUC calculations.
Calculation
Compute last AUC This option allows the inclusion of the last triangle of the AUC from
triangle, if last value is the last measured value (t-last) to the first BLQ data point for datasets
BLQ with the trailing measurements being BLQ. This partial AUC is
included in the AUC value reported for that profile
Specifying Infusion (applicable To specify IV infusion:

to IV infusion only)
1. Select the Infusion check box.
3. Select Inf Value and enter a numerical value for the infusion
in the adjacent field.
4. Select Inf Var Name and select the appropriate variable name
for the infusion from the available list. Select this option if
the variable already exists in the dataset numerical field (All
Variables view in the Study pane).
6. Under the Selected Unit column, specify Time (e.g. h),

Concentration (e.g. mg/mL), a Dose (e.g. mg), AUC (e.g.
M.h) and any other required units from the drop down list
the units under the Display Label column.

• Select Variable Name and select the appropriate variable

name for the molecular weight from the available list.
Select this option if the variable already exists in the
dataset numerical field (All Variables view in the Study
pane).
• Select Value and enter a numerical value for the

molecular weight in the adjacent field.

IV Infusion Template The following section provides information on the IV Infusion

template.
Inputs and Outputs The following input and output information can be found in the
Study Info worksheet in the Study pane:
• Dose – Amount of drug in the galenic formulation
• Tinf – Infusion duration
• T – Time
Methods The Set Column Unit and Make ConcUnit methods are used to
and inserts the correct final measurement units.
AUC: partial area under AUClast: AUC from t=0 to tlast (last sampling time)
the curve
AUCcum: accumulated AUCextra: extrapolated AUC

AUC
AUMC: partial area AUCtot: AUC total (=AUClast+AUCextra)

under the moment
curve
AUMCcum: %AUCextra: percentage of AUC extra with respect to AUC total

accumulated AUMC
R: correlation coefficient AUMClast: AUMC from t=0 to tlast.

of linear regression on
log transformation

G: criteria used to AUMCextra: extrapolated AUMC

estimate Lz
G: Criteria used for C0 extrapolation and Lz calculation.
Rsmooth: Ratio between AUC below the curve and AUC above the
curve. The output value is always between 0 and 1. A small difference
between AUC below the curve and AUC above the curve reveals a good
estimation of the real AUC and a good sampling time.
Raccurate: Raccurate =1-AUCpartial/AUC
where:
AUCpartial is the value that has the largest difference from AUC
(AUCpartial was calculated using n-1 data points.)

Computed CLast: Last concentration point estimated using the linear

equation obtained from linear regression on log-transformed data
TLast : Last time point
B: Slope of the linear equation on log-transformed data
AUCall: If the last sample is at normal status, missing and outlier then,
AUCall=AUClast
If the last sample is BLQ or zero, or the last several data points are BLQ
or zero, AUCall is calculated as:
AUCall=AUClast+AUCtriangle,
where:
AUClast is from t=0 to the last normal status data
AUCtriangle is:
Clast
AUCtriangle = ( t last +1 − t last )
2
Clast can be predicted or observed value. tlast+1 is the first BLQ or Zero
data sampling time. There are two outputs from two options in AUCall
calculation:
to use Clast predicted value, AUCall(CPred)
to use Clast observed value, AUCall(CObs)

Equations Equations used by the methods:
ln 2
T1 =
2 Lz
AUMC T inf
MRT = −
AUC 2
Dose
Cl = AUC
Dose
Vz =
AUC ⋅ Lz
Dose ⋅ AUMC
Vss =
AUC 2
Dose ⋅ MRT
Vss =
AUC
Viewing an Example of This example contains data for one dataset. An infusion of
NCA - IV Infusion 7842.35 mg was administered over a period of 0.16667 hours.
The concentration-time course was sampled from the plasma.
Template
Concentration is expressed in mg/L and time is expressed in h.
To view an example of NCA - IV infusion template:
dialog appears.

Figure 8-10. New Analysis Dialog – IV Infusion
2. Select IV Infusion analysis found on the Non-

Compartmental tab.
4. Click OK.
Note For this example, we entered data into the relevant

template and saved it as a .kdb file. If you open the
corresponding file in the template subdirectory you will see
no data. It is ready for your experimental data. ▲
The dataset appears as follows, containing only the raw data

that we entered before sending Kinetica:

Figure 8-11. Example – IV Infusion Dataset
Before running the analysis examine the graph displaying the

time versus concentration values.
5. Click the Dataset Graph button found in the Dataset pane.


Figure 8-12. Example – Dataset Graph


Figure 8-13. AUC * Method Global Options
9. Modify your selections by adjusting the AUC and Units

options, as required. For more information, see the section,
Modifying AUC* Options.
10. Select Calculate One from the Dataset menu to run the
analysis.
The Lz plot is displayed automatically when the “Show Lz

Plot” check box is selected. Deselect the check box if you do
not want to display the Lz plot.

Figure 8-14. Example – Lz Plot Graph

Calculate All from the Dataset menu. The results for all
datasets are calculated in batch mode and displayed using the
Gallery feature. You can then make universal changes to the
appearance of your graphs. ▲
11. Select the T, C, and AUCcum columns.
Note To select columns that are non-contiguous, hold

down the Ctrl key while selecting the non-contiguous
column(s). ▲
12. Select the Show One Graph button. The following graph
appears:

Figure 8-15. Example – Dataset Graph – IV Infusion
Exporting Results to Excel To export your results to Excel:
1. Load Excel.
2. Select the columns or rows you want to export from Kinetica.
3. Select the Export to Excel button.
4. Switch to Excel to see the data displayed in a worksheet.

Extravascular Route The following section provides information on the Extravascular

Route Template.
Template
Dose – Amount of drug in the galenic formulation
• T – Time
Methods The Set Column Unit and MakeConcUnit methods are used to
and inserts the correct final measurement units required.
Viewing an Example of This example contains data for one dataset. A drug dose of
NCA - Extravascular 8043.43 nmol was orally administered. The concentration-time
course was sampled from the plasma. Concentration is expressed
Template
in mg/L and time is expressed in h.
To view an example of the NCA - Extravascular template:
dialog appears.

Figure 8-16. New Analysis Dialog – Extravascular
2. Select Extravascular analysis, found on the Non-

Compartmental tab.
4. Click OK.
Note For this example we entered some data into the

relevant template and saved it as a .kdb file. If you open the
corresponding file in the template subdirectory you will not
see any data. It is ready for your own experimental data. ▲
The dataset group appears as follows, containing only the raw

data.

Figure 8-17. Extravascular Dataset
5. Before running the analysis, examine a graph of the time

versus concentration values by selecting the dataset graph icon
on the left pane.
6. Select the T and C columns.

The following appears:

Figure 8-18. Example – Extravascular Dataset Graph


Figure 8-19. AUC * Method Global Options Dialog
11. Modify your selections by adjusting the AUC and Units

options, as required. For more information, see the section,
“Modifying AUC* Options” in this chapter.
analysis.
Note The Lz plot is displayed automatically when the check

box is selected. Deselect the check box if you do not want to
display the Lz plot. ▲

Figure 8-20. Example - Lz Plot Display

datasets will be calculated in batch mode and displayed using
the Gallery feature. You can make universal changes to the
appearance of your graphs. ▲

column(s). ▲
14. Select the Show One Graph button on the toolbar. The
following graph appears:

Figure 8-21. Example – Extravascular Dataset Graph
1. Load Excel.
3. Select the Export to Excel button on the Kinetica toolbar.
4. Switch to Excel. The data is displayed in a worksheet.

Summary of First The PK parameters available for each administration route are
listed in the following table.
Dose PK Parameters
for each
Administration Route
Route of Administration
IV Bolus IV Infusion IV Extravascular
PK Parameters
Lz Lz Lz
ln 2 ln 2 ln 2
T1 = T1 = T1 =
2 Lz 2 Lz 2 Lz
Tmax Tmax
Cmax Cmax
AUC AUC AUC
AUMC AUMC AUMC
AUMC AUMC T inf AUMC

MRT = MRT = − MRT =
AUC AUC 2 AUC
Dose Dose Cl Dose

=
Cl = AUC Cl = AUC F AUC
Dose Dose Vz Dose

Vz = Vz = =
AUC ⋅ Lz AUC ⋅ Lz F AUC ⋅ Lz
Dose ⋅ AUMC Dose ⋅ AUMC Vss Dose ⋅ AUMC

Vss = Vss = =
AUC 2 AUC 2 F AUC 2
Dose ⋅ MRT Dose ⋅ MRT Vss Dose ⋅ MRT
Vss = Vss = =
AUC AUC F AUC
For extravascular administration, bioavailability, F, is generally

unknown; therefore, parameters containing F are denoted as:

Cl Vz Vss
, and
F F F
The real MRT is expressed as:
AUMC ⎛ 1 ⎞
MRT = − ⎜ Tlag + ⎟
AUC ⎝ Ka ⎠
(with Tlag = lag-time, and Ka = absorption constant rate) and not
AUMC
MRT =
AUC
But as Tlag and Ka are generally unknown, the following

simplified formula is used:
AUMC
MRT =
AUC

Steady State The Steady State template allows you to obtain pharmacokinetic
(PK) parameters by analyzing data using one dosing interval time
Template (Tau). Two methods allow you to calculate PK parameters:
• The AUC Steady State hard-coded method selects one dosage

interval for data analysis.
• The ClearanceSS soft-coded method determines estimation of

clearance.
• The AUC steady-state with Lz hard-coded method is an

extension of the AUC steady-state method. It is designed to
perform terminal phase regression and obtain associated
pharmacokinetic parameters.
The templates provided for steady state enable analysis of the IV

Bolus, IV Infusion and Extravascular administration routes.
The PK parameters computed in the steady state template are

Parameter Description
Tau Dosage interval time
Cmax Maximum drug concentration during the selected dosing interval
Cmin Minimum drug concentration during the dosing interval
Tmax Time corresponding to the first peak of concentration
AUCss Area under the curve during the selected dosing interval at steady state
AUMCss Area under the moment curve during the selected dosing interval at steady state

Caverage Mean or average steady state drug concentration expressed as:
AUCss
Tau
%ptf
Peak-through-fluctuation expressed as:
C max − C min
% ptf = 100 ⋅
Caverage
%AUCdf Percentage-area-fluctuation expressed as:
%swing Degree of fluctuation expressed as:
C max − C min
% swing = 100 ⋅
C min
Clss Clearance at steady state expressed as:
ma int enancedose
Clss =
AUCss
(it is Clss/F when the bioavailability F is not equal to 1)
Tstart Dosing interval start time
Tend Dosing interval end time
HVD Half-value duration is the period at which the drug concentration is above half
Cmax value.

AUClast AUC from t=Tstart to Tend (last sampling time)
AUCextra extrapolated AUC
AUCtot AUC total (=AUClast+AUCextra)
%AUCextra percentage of AUC extra with respect to AUC total
Lz The elimination rate based on the slope of the terminal phase regression
R linear regression coefficient
G Criteria used for C0 extrapolation and Lz calculation.
Rstart First point used for Lz calculation
Rend Last point used for Lz calculation
Rnbpoint Number of points used in Lz calculation
Rsmooth Ratio between AUC below the curve and AUC above the curve. The output
value is always between 0 and 1. A small difference between AUC below the
curve and AUC above the curve reveals a good estimation of the real AUC and a
good sampling time.
Raccurate Raccurate =1-AUCpartial/AUC
where:
AUCpartial is the value that has the largest difference from AUC (AUCpartial
was calculated using n-1 data points.)
ComputedCLast Last concentration point estimated using the linear equation obtained from
linear regression on log- transformed data
Tlast Last time point
Thalf Half-life of elimination
Cstart Concentration at t=tstart

A Intercept of the linear equation of log transformed data
B Slope of the linear equation of log transformed data
R2 Coefficient of determination whose square root is the correlation coefficient
Clss Clearance at steady state expressed as:
ma int enancedose
Clss =
AUCss
(it is Clss/F when the bioavailability F is not equal to 1)
Vss Volume of distribution at steady state is calculated as Dose/(AUCss*Lz)
MRTlast Steady state mean residence time is calculated as Vss/Clss

is calculated as:
Accumulation
1
Rac = , where τ is Tstart-Tend
1 − e − Lz*τ

Dose (steady-state) – Maintenance dose
• T – Time
and inserts the correct final measurement units required.

Methods Column and Variable Outputs
AUC Steady State AUC = partial area under the curveAUCcum = accumulated area under the
curve
AUMC = partial area under the moment curve
AUMCcum = accumulated area under the moment curve
Tau = dosage interval time
Cmax = maximum steady state drug concentration during a dosing interval
Cmin = minimum steady state drug concentration during a dosing interval
Tmax = maximum time corresponding to Cmax
AUCss = area under the curve during a dosing interval at steady state
AUMCss = area under the moment curve during a dosing interval at steady
state
Caverage = mean or average steady state drug concentration
%ptf = peak-through-fluctuation
%AUCdf = percentage-area-fluctuation
%swing = degree of fluctuation
Tstart= dosing interval start time
Tend= dosing interval end time
Clearance Steady Clss = clearance at steady state

State

Viewing an Example of This example contains data for one dataset. At steady state a drug
NCA - Steady State dose of 100 mg was orally administered. The concentration-time
course was sampled from the plasma at steady state.
Template
Concentration is expressed in mg/L, and time is expressed in h.
The PK parameters at steady state were obtained at the dosage
interval time (i.e. tau=12h).
To view an example of the NCA - Steady State Template:
dialog appears.
Figure 8-22. New Analysis Dialog – Steady State Template
2. Select the Steady State analysis found on the Non

Compartmental tab.
4. Click OK.
Note For this example we entered some data into the relevant
template and saved it as a .kdb file. If you open the corresponding
file in the template subdirectory you will not see any data. It is
ready for your own experimental data. ▲

The dataset group appears as follows, containing only the raw

data that we entered before delivering Kinetica:
Figure 8-23. Dataset Group – Raw Data
Before running the analysis, examine a graph of the time versus

concentration values:


Figure 8-24. Dataset Graph
3. In the Methods column, select AUC Steady State*.

AUC Steady State Method Global Options dialog appears:

Figure 8-25. AUC Steady State Method Global Options

Dialog
5. Enter 48 for t start and 60 for t end. You are now specifying
to calculate the steady state parameters between time 48 and
60 hours only.
6. Select Calculate One from the Dataset menu. The results are
displayed. Scroll down to find the computed values.
Note If you have multiple datasets to analyze, select

datasets will be calculated in batch mode and displayed in the
groups. You can scroll through the datasets to see the results
for different subjects. ▲

Figure 8-26. Calculated Results Display
You can continue to review the data using the graphical tools:

column(s). ▲
2. Select the Show One Graph button found on the toolbar.


Figure 8-27. Single Graph Display
1. Load Excel.
3. Select the Export to Excel button found on the toolbar.
4. Switch to Excel. The data is displayed in a worksheet.
Modifying AUC Steady Some methods contain options that you can modify. In this
State * Options template, you can only modify the AUC Steady State* method.
To modify options for the AUC steady state* method:
1. Select the Methods pane in Kinetica.
2. Locate AUC Steady State * and click Set in the corresponding

Global Options column.

Figure 8-28. Modifying AUC Steady State* Options
3. The AUC Steady State Method Global Options dialog

appears:
Figure 8-29. AUC Steady State Method Global Options

Dialog
4. Select the Options tab, and specify the following information:

AUC Computation Select mixed log-linear, log-linear, or trapezoidal.
BLQ Data Select Default, Set as 0, or Set as missing. For more information, see the
section, “AUC* Options” in the chapter, “Working with Methods and
Models”.
Note In order to flag data as BLQ, you must first run the analysis, then
identify each undetectable data point with a "less than" sign (<) before
selecting a BLQ Data indicator. For more information, see the section,
“Displaying Non-Detectable Data Points” in the chapter, “Working with
Graphs.” ▲
AUC Cumulated Select No Interpolation or Interpolation. Use an interpolation rule when

missing values are found.
AUC Log Start Time Enter a start time for AUC calculation (by logarithmic method). By
default, Kinetica uses the time corresponding to Cmax in the interval.
t start Enter the time corresponding to the beginning of Tau. If you do not enter
a value, Kinetica uses the time corresponding to the first data point.
t end Enter the time corresponding to the end of Tau. If you do not enter a
value, Kinetica uses the time corresponding to the last data point.
5. Select the appropriate input and output units from the Units
tab.
6. Click OK to save the selections and exit the dialog.

The AUC steady-state This section describes the steady-state algorithms and how they
can be applied to any type of steady-state dose administration.
with Lz* and AUC One way to perform non-compartmental analysis is by applying a
steady-state* method to the steady-state time-concentration data. The table
below shows the important differences between AUC steady-
Methods
state* and AUC steady-state with Lz*.
AUC steady-state AUC steady-state with Lz
Multiple-dose profile allowed Profile should contain only the steady-state

dosing interval which could be the last dose
profile
Computes exposure between any specified start and Computes AUC steady-state based on dosing
end time interval tau
Dose is not required in the method Steady-state dose is required
Half-life and clearance are not computed Half-life, clearance, volume of distribution
and parameters derived from terminal phase
regression and input dose are computed
Lz graphs not enabled Lz graph with user-defined start and end of

regression enabled
A step-by-step example using the AUC steady-state with Lz

method is given below:
1. Import time-concentration data
2. Insert a dataset numeric field called Dose
3. Click Insert Method and select AUC Steady State with Lz

Figure 8-30. Selecting AUC Steady State * with Lz method
4. Map the Input columns and variables for X, Y and Dose
5. Make changes to the output column and variable names, if

you wish.
6. Click Insert and then click OK.
7. Now that you have successfully inserted the AUC* method,

select the Method pane on your left navigation bar.
8. Click the Set button of the AUC Steady State* with Lz

method under the Global Options.
9. The AUC Steady State with Lz Method Global Options

dialog box appears to allow you to set the computation
settings for the NCA. The Unit tab allows you to set the
input and output parameter units.
10. Once the data are set-up, you may start analysis by clicking
the double-head icon: .

Figure 8-31. Setting Global Options for the AUC Steady State
with Lz method
can be estimated using trapezoidal rule (linear rule), log linear
and mixed log linear. The AUMC calculation follows the same
rule as AUC.
• Mixed log linear – refers to the computation method wherein

all ascending phases are computed in a linear manner and all
descending phases are computed based on their log values;

• Log linear – computes all values prior to Cmax in a linear

computation;
• Trapezoidal – computes all values in a linear manner.
AUC start Calculation The AUC start calculation handles the first cell of the X and Y
column. This computation determines the value for the Y column
when the independent variable (time) is the start time,
consequently determines whether the route of administration is
IV bolus or extravascular. These are the following options
available:
• cStart = c1 – applies to IV Bolus, where the concentration at

the missing zero or first time point assumes the same
concentration for the first collection.
• cStart = 0 – assumes that the drug concentration at the zero

time point is zero. This condition applies to IV Infusion and
• Extrapolated C0 – applies to IV Bolus, where the

concentration at the zero time point is extrapolated based on
the log values of the first three collected time points.
• No AUC0 computation – assumes no computation of the

area under the concentrations between the zero time point
and the first collected time point. Computation of the area
(AUC) starts at the first available concentration data
• cStart = cTau – use the corresponding concentration value for

whatever “T end” is supplied
• cStart based on selected t – the “T for Cstart” is enabled to

allow the user to input the time; the corresponding
concentration will be used as the starting concentration for
the profile.

AUC Infinity The AUC from the last quantifiable measurement to infinity
called AUCextra can be estimated using the following options:
Computed Clast/Lz, Observed Clast/Lz, and no AUCinf
calculation where Lz is the slope of the terminal phase using log
scale.
• Computed Clast/Lz – the computation of the extrapolated

area beyond the last concentration is based on the estimated
last concentration obtained from the regression divided by the
slope of the regression line;
• Observed Clast/Lz – the extrapolation of the area beyond the

last concentration is based on the observed last concentration
divided by the slope of the regression line
• No AUCinf computation – AUC from zero to infinity is not

computed at all.
AUC Cumulated Ci missing and AUCcum (AUC accumulated) can be estimated

using the following options: Interpolation and No interpolation.
Under AUCcum, the two options are Interpolation or No
Interpolation. Interpolation applies to cases where there are
missing data; Kinetica allows you to use linear interpolation
(between the preceeding point and the next point) to estimate the
missing value.
values: AUC Log Start Time, C0 Start Time and Lz Start Time.
• AUC Log Start Time – entry will override Tmax for the start
of log AUC computation when AUC computation selected is
log linear; entry should be a time point in the X column;
• T start – entry is used the start time for the steady-state

profile;
• T end – entry is used as the end time for the steady-state

profile; the difference between T end and T start becomes the
Tau or dosing interval;

• Lz Start Time – entry will be used as the start of terminal

phase regression and will override the optimization method
based on greatest G-value for the selection of start of terminal
regression;
• Lz End Time – entry will be used as the end of terminal

phase regression.
• Extrapolated CStart Start Time – entry will be used as the

starting time for the backward regression to the Tstart for IV
bolus administration; by default, three time points are used in
the extrapolation to determine the starting concentration of
the steady-state profile.
BLQ Handling The BLQ Data option lists different ways how to handle below
the limit of quantification data by selecting:
less than symbol.
• Set as 0: Data with “<” will assume the value of 0.
• Set as missing: Data with “<” will be treated as missing.

data as 0.
• User-defined LLOQ, if checked, will override the BLQ data

option and enable user to map the column for the LLOQ
values and set BLQ to LLOQ, LLOQ/2, LLOQ/3 and
LLOQ/4.
Infusion Box The Infusion check box, if checked, allows you to set the infusion
duration time or map to a dataset a numeric variable for the
infusion duration. Note that you must enter values in the same
units as the time unit. Select the Inf Value radial button if you
wish to enter a value manually, or select the Inf Var Name radial
button if you wish to map to a specific field.

Other Check Boxes The remaining check boxes available in the AUC* Method
Global Options window are described below.
Exclude Tmax in Lz calculation If the most optimized G-value lies at the Tmax for the start of
terminal phase regression, the next time point with the most
optimized G value following Tmax will be used instead, if the
box is checked.
Compute Last AUC triangle If the last value is BLQ, with Compute Last AUC Triangle
checked, AUClast will include the AUC of the last triangle if the
value following the last normal data is flagged as BLQ. Note that
AUCall(Obs) always include the last triangle area if the value
following the last normal data is flagged as BLQ.
Use outliers in AUC calculation If checked, any cell marked as an outlier will be included in the
computation of AUC but not used in the terminal phase
regression.
Show Lz Plot If checked, the individual profile with the estimated terminal
phase regression line will be plotted in the gallery view every time
AUC* is run. This box is checked by default.
Multiple Tmax If there is more than one largest concentration value, you may use
the first or last Cmax to report Tmax, or use a median Tmax
value.

The Sparse AUC* To perform sparse AUC computation, you need datasets to be set
up such that there are three columns available for Time,
Method Concentration and Animal ID. In the example below, each time
point has three concentration data. Notice that the time and
concentrations are repeated and taken from different animals.
When you import the data into Kinetica, you need to group them
such that each individual dataset contains the grouping variable
to perform the composite analysis. For example, the specific
dataset can be created by grouping animals by gender that had
taken the same dose. The Sparse AUC example in the
Kinetica\Data folder shows how the method expects the data to
be set up.
Time Concentration Animal ID
0 0 101
0 0 102
0 0 103
0.5 4 104
0.5 1.3 105
0.5 3.2 106
1 4.69 107
1 2.07 108
1 6.45 109
2 6.68 104
2 3.83 105
2 6.08 106
4 4.69 101
4 4.06 102

Time Concentration Animal ID
4 6.45 103
6 8.13 104
6 9.54 105
6 6.29 106
8 9.36 107
8 13 108
8 5.48 109
12 5.18 107
12 5.18 108
12 2.79 109
24 1.06 107
24 2.15 108
24 0.827 109
The algorithm used to compute the standard error of the AUC

values is based on the trapezoidal (or linear) rule from sparse
sampled data. The input variables are the sampling time and the
individual drug concentration from plasma or tissue. Note that
even though this method computes AUC based on the log linear
or trapezoidal rule, it does not apply logarithmic transformation
of the data when computing the standard error of the AUC.
The following steps provide a general procedure to perform sparse

AUC computation:
1. Import time-concentration data and animal ID.
2. Insert a dataset numeric field called Dose.

3. Click Insert Method and select Sparse AUC*.
4. Map the input columns for X, Y and Animal ID.

wish.
7. Now that you have successfully inserted the Sparse AUC*

method, select the method pane on your left navigation bar.
8. Click the Set button of the Sparse AUC* method under the
Global Options
9. The Sparse AUC* Method Global Options dialog box

appears to allow user to set the computation settings for the
computation. And the Unit tab allows user to set the input
and output parameter units.
10. Once the data are set-up, you may start analysis by clicking
the double head icon: .

Figure 8-32. Sparse AUC* Method Global Options dialog
can be estimated using trapezoidal rule (linear rule), log-linear
rule as AUC.
• Mixed log linear – refers to the computation method wherein

• Log linear – computes all values prior to Cmax in a linear

computation.
• Trapezoidal – computes all values in a linear manner.

AUC Start Calculation The AUC from 0 to the first sampling time called AUC start can
be estimated using the following options: C0=0, C0=C1,
available:
• c0 = c1 – applies to IV Bolus, where the concentration at the

zero time point assumes the same concentration for the first
collection.
• c0 = 0 – assumes that the drug concentration at the zero time

point is zero. This condition applies to IV Infusion and


and the first collected time point.

values – AUC Log Start Time, C0 Start Time and Lz Start Time.
• AUC Log Start Time – entry will override Tmax for the start
of log AUC computation when AUC computation selected is
log linear; entry should be a time point in the X column.
• Lz Start Time – entry will be used as the start of terminal

phase regression and will override the optimization method
based on greatest G-value for the selection of start of terminal
regression.
• Lz End Time – entry will be used as the end of terminal

phase regression.
• C0 Start Time – entry will be used as the starting time for the
backward regression to the 0 time point for IV bolus
administration; by default, three time points are used in the
extrapolation to determine the initial concentration.
BLQ Handling The BLQ Data option lists different ways how to handle below
• Default – Data with “<” and assumes the value proceeding

the less than symbol.
• Set as 0 – Data with “<” will assume the value of 0.
• Set as missing – Data with “<” will be treated as missing.
• Box for BLQ before first non-zero normal data = 0 – if

data as 0.
• User-defined LLOQ – if checked, will override the BLQ data

LLOQ/4.

Use Outliers Check Box Use outliers in AUC calculation – if checked, any cell marked as
an outlier will be included in the computation of AUC but not
used in the terminal phase regression.

The Superposition – The superposition – variable dosage method or the overlay

technique allows you to predict concentration data after multiple
Variable Dosage dosing based on single dose data. The method assumes linearity
Method and proportionality in the data to allow a proportional increase in
the dose, if a different dose is given at any interval.
To perform the superposition algorithm, your datasets need to be

set up such that the data contains the time and concentration for
a single dose, as well as the dose for the profile. Also make sure
that you have the Admin dose and Admin time available. The
Admin Dose column should contain the multiple doses that you
wish to simulate while the Admin Time should contain entries
that correspond to the time at which the multiple doses are
administered. The Superposition example in the
\\Kinetica\Data\Non Compartmental folder contains an example
of how the method expects the data to be set up.
The table below shows an example dataset with a set of time-

series for sampled concentration and another set of time-series for
dose administration.
Time (h) Concentration AdminDose (mg) AdminTime (h)

(ng/mL)
0 0.099 200 0
0.25 2.6546 200 6
0.5 4.09063 300 10
0.75 4.85247
1 5.21021
1.25 5.32743
1.5 5.30317
1.75 5.19728
2 5.0459
2.25 4.87076

Time (h) Concentration AdminDose (mg) AdminTime (h)

(ng/mL)
2.5 4.68487
2.75 4.49598
3 4.3086
3.25 4.12536
3.5 3.94768
3.75 3.77631
4 3.61156
4.25 3.4535
4.5 3.30206
4.75 3.15708
5 3.01835
5.25 2.88565
5.5 2.75874
5.75 2.63739
6 2.52137
1. Import time-concentration data and dose information.
2. Insert two columns called Admin Dose and Admin Time by

selecting Insert from the menu and then select Column.
3. Click Insert Method and select Superposition – Variable

Dosage.

4. Map the input columns for X, Y, Dose, Admin Time and

Admin Dose.

wish.
7. Now that you have successfully inserted the Superposition –

Variable Dosage method, select the method pane on your left
navigation bar.
8. Click the Set button of the Superposition – Variable Dosage

method under the Global Options
9. The Superposition – Variable Dosage Method Global

Options dialog box appears to allow you to set the
computation settings for the computation. The Unit tab
allows you to set the input and output parameter units.
10. Once the data are set up, you may start analysis by clicking
the double head icon: .

Interpolation Method The AUC from time zero to the last quantifiable measurement
can be estimated using trapezoidal rule (linear rule), log-linear
rule as AUC.
• Mixed log linear: refers to the computation method wherein

• Log linear: computes all values prior to Cmax in a linear

computation.
• Trapezoidal: computes all values in a linear manner.
C0 Handling The time from 0 to the first sampling time called C0 can be
estimated using the following options: C0=0, C0=C1,
available:
• c0 = c1 – applies to IV Bolus, where the concentration at the

zero time point assumes the same concentration for the first
collection.
• c0 = 0 – assumes that the drug concentration at the zero time

point is zero. This condition applies to IV Infusion and


and the first collected time point.

BLQ handling The BLQ Data option lists different ways how to handle below
• Default – Data with “<” and assumes the value proceeding

the less than symbol;
• Set as 0 – Data with “<” will assume the value of 0;
• Set as missing – Data with “<” will be treated as missing;
Last Simulated Time Point Last Simulated Time Point – enter the last time point where
simulation stop
Number of Output Data You need to tell the method the total number of points to
Points simulate. The method takes the last simulated time point and
divides it by the total number of points minus 1 to increment the
time points from the first time point all the way to the last
simulated time point. Therefore, you will need to provide n+1
points to include zero time point. For example, if you want to
simulate every 0.125 hour up to 24 for the independent variable,
the value for the total number of output data points is 24 * 23 + 1
= 193.
Start and End Times Regression Start Time: entry will be used as the start of terminal
phase regression and will override the optimization method based
on greatest G-value for the selection of start of terminal
regression.
Regression End Time: entry will be used as the end of terminal

phase regression.

Working with the The NCA Assistant is a tool for high throughput non-
compartmental analyses, enabling you to interactively analyze
NCA Assistant data using a graphical interface. You can view the time versus
concentration data values next to the subject curve. You can
customize the appearance of the plot, selecting the style, width,
and color for the line. You also have the option to flag outlier and
BLQ data points. Selections can be applied to single datasets or
all datasets in the study. The non-compartmental parameters are
recalculated whenever options are modified.
NCA Assistant Wizard The NCA Assistant wizard is accessed from the Kinetica
Welcome dialog or from the toolbar any time during a working
session.
The NCA Assistant wizard is a series of dialogs that simplifies

non-compartmental analyses and guides you through the process
step-by-step. You: specify X and Y input columns and variables
for the analysis, global AUC rules and options, units for input
and output variables, and local AUC options.
To use the NCA Assistant wizard, read the instructions in each

dialog to help you enter information, and follow the steps in the
procedure. You can move back and forth between the dialogs and
change information as required until you complete the wizard.
You can exit without saving the information at any point before
completing the wizard by clicking Cancel.
The NCA Assistant wizard has 5 steps. Steps 1, 3, and 5 can be

completed by following the instructions in the dialog and in the
procedure. Steps 2 and 4 are explained in detail in their own
sections.
Note The NCA Assistant wizard links to the first defined

AUC* method it locates in the list of methods. ▲

NCA Assistant – Step 2 of 5 This dialog is used to specify the calculation rules to apply to a
Dialog selected study. The available options are listed in the following
table.
Calculation Rule
AUC Mixed Log Linear
Log Linear
Trapezoidal
AUC0 c0=0
c0=c1
Extrapolated c0
No AUC0 computation
AUCinf ComputedClast/Lz
ObservedClast/Lz
No AUCinf computation
AUCcum No interpolation
Interpolation

Calculation Rule
BLQ Data Select Default, Set as 0, or Set as missing. For

more information, see the section, “AUC *
Options” in the chapter, “Working with
Methods and Models”. If you do not specify
a BLQ Data indicator, the "Default" option
will be used for all AUC computations, by
default.
Note In order to flag data as BLQ, you

must first run the analysis, then identify each
undetectable data point with a less-than sign
(<) before selecting a BLQ Data indicator.
For more information, see the section,
“Displaying Non-Detectable Data Points” in
the chapter, “Working with Graphs”.
Alternatively, you can identify undetectable
data points in the NCA Assistant – Step 4 of
5 dialog. For more information, see the
section, “Flagging Data as BLQ
(Undetectable)” in this chapter. ▲
Infusion User-defined selection (available only if the

Variable route of administration is IV infusion)
NCA Assistant – Step 4 of 5 This dialog is used to select local and global AUC calculations to
Dialog apply to a selected study. You can also view various datasets
contained in the study, traversing through each dataset to view
the results. These options are described in the following table.
Option Description
View data During an analysis, you can view the graphical

plot only, or the graphical plot and the X and
Y column values used to plot the graph. To do
this, select or deselect the View Data check
box. This option is useful when combined
with the ability to flag outliers and/or BLQ
data points since the flags become visible in
the Y data column

Option Description
Y-Log scale Sets the display for the Y axis to log scale
Local options The Local options area of the dialog is used to

specify the following:
• T for AUC log
• T for Lz estimate
• T for Co estimate
• Infusion Value.
These options can be set individually for each

dataset.
Recalculate Re-analyze all the AUC parameters.
Apply to all Apply the current calculation options to every

dataset in the study.
Results area Contains a list of computed AUC parameters.

These calculations are derived from user-
defined selections made in real-time on the
graphical plot.

Specifying Time for AUC You can specify a start time for AUC log calculations by plotting
Log a line indicator on the graphical plot (a blue solid line). You can
perform this function by entering a time value in the t for AUC
log field.
Your plot should resemble the following:
Figure 8-33. Example – Specifying Time for AUC Log

Specifying Time for You can specify a start time for terminal phase regression analysis
Terminal Phase by plotting a vertical line on the graphical plot (plots a green solid
line). To perform this function, click on the appropriate
Regression
timepoint to start the Lz plot, or enter a value on the t for Lz
estimate field (see figure below). Each time you move the vertical
line, the non-compartmental parameters are re-calculated and the
results are updated. If you do not specify a terminal phase
regression start time, the NCA Assistant will use an automatic
calculation to find a suitable result.
Figure 8-34. Example – Specifying Time for Terminal Phase Regression
Specifying Time for Initial You can specify a start time for initial phase regression analysis by
Phase Regression plotting a line indicator (a green broken line) on the graphical
plot (see figure below). You can perform this function by entering
a time value in the t for C0 estimate field. If you do not specify an
initial phase regression start time, the NCA Assistant will use an
automatic calculation to find a suitable result.

Figure 8-35. Example – Specifying Time for Initial Phase Regression
Flagging Data as Outlier You can specify whether a data point is an outlier or not,
therefore, including or excluding the value from the analysis. If
you flag a data point as an outlier, the outlier data point changes
to a blue circle. Each time you exclude or include a data point the
non-compartmental parameters are re-calculated and updated,
and the terminal phase regression line indicator is automatically
moved.
The original data point values are never deleted or amended. A

flag is simply attached to the data value, as can be seen by
selecting the View Data check box.

Figure 8-36. Example – Flagging Data as Outlier

Flagging Data as BLQ You can specify whether a data point is below the limit of
quantification (BLQ or undetectable) or not, thereby including
(Undetectable) or excluding the value from the analysis. Each time you exclude
or include a data point, the non-compartmental parameters are
re-calculated and updated, and the terminal phase regression line
indicator is automatically moved.
The original data point values are never deleted or amended. A

flag is simply attached to the data value, as can be seen by
selecting the View Data check box.
The default BLQ symbol appears as an hourglass-like shape.
Figure 8-37. Example – Flagging Data as BLQ

Performing Non- To perform non-compartmental analysis using the NCA

compartmental Analysis assistant:
Using the NCA Assistant
1. Launch Kinetica. The Welcome to Kinetica dialog appears:
Figure 8-38. Welcome to Kinetica Dialog
2. Select NCA Assistant and click OK. The New Analysis dialog
appears.
Figure 8-39. NCA Assistant with Extravascular assistant selected and Open with Data checkbox
checked.

3. Select a non-compartmental analysis type. To open the

template with example data, select the Open with Data check
box.
Note If you would like your own NCA template to appear

in the NCA Assistant, before starting Kinetica place your
template (a .ktp file) in the Program Files\Kinetica\Data
directory. ▲
4. For this example, we select the Extravascular template, check

the Open with Data box, and click OK.
If you do not use the Open with Data option, the following
message appears:
Figure 8-40. Kinetica query when you do not select Open with Data.
Do one of the following:
• Click Yes to enter the data manually.
• Click No. Import Assistant imports the data for you from
a foreign file or database. The assistant only works if the
study contains data.
5. After clicking OK with the Extravascular template, Open

with Data selected, the NCA Assistant - Step 1 of 5 dialog
appears.

Figure 8-41. NCA Assistant – Step 1 of 5
6. Select the X and Y input columns for the plot from the X
column and Y column list boxes. By default, Kinetica selects
the first two columns of the first worksheet.
7. Specify the route of drug administration from the Route list

box.
8. Specify the dose from the Dose list box and click Next. The
NCA Assistant - Step 2 of 5 dialog appears.

9. Select the appropriate AUC options, BLQ indicator (see the

section BLQ handling for more on BLQ), and Infusion
Variable (if required) from the available lists and click Next.
The NCA Assistant - Step 3 of 5 dialog appears.

10. Specify the input units (Time, Concentration and Dose) and
select the appropriate units for the output variables.
11. Click Next. The NCA Assistant - Step 4 of 5 dialog appears.

A plot of the X and Y columns appears, displaying the
regression line derived from an automatic linear regression
calculation.

12. Select the options to use for the AUC calculations, as

required.
Customizing the Plot To customize the plot, right-click anywhere in the graph, select
Graph Properties and then the appropriate selection from the
second popup menu. Make modifications as required. For more
information, see the section, Dataset Graph Options in the
chapter, Working with Graphs.

Flagging Outlier Data Points To flag outlier data points, right-click the appropriate data point
(shown as Point# x value; y value) and select Outlier from the
popup menu. The data point changes to a blue circle.
Flagging BLQ Data Points To flag BLQ data points, right-click the appropriate data point
(shown as Point# x value; y value) and select Undetectable from
the popup menu. The data point changes to an hourglass-like
shape.
Sending a Graph to the Gallery To send a graph to the Gallery:
1. Right click anywhere in the graph and select Send to Gallery.

For more information, see the section, “Working with the
Graph Gallery” in the chapter, “Working with Graphs.”
2. Click Next. The NCA Assistant – Step 5 of 5 dialog appears:
Figure 8-45. NCA Assistant – Step 5 of 5 dialog

3. Click Finish to conclude the NCA Assistant wizard.
4. Kinetica displays the graph Gallery view with the new graph
added.

9. Performing Compartmental
Analysis
Kinetica is a flexible tool for all kinds of pharmocokinetic/
pharmacodynamic (PK/PD) fitting. Many methods, models and
templates are included with the software, and we have designed
an interpreted language called Kinetica Basic that enables you to
create any model you require. A differential equation solver is
supplied and a visual designer enables you to generate the basic
code for differential systems interactively drawn on your screen.
This chapter guides you through the available models, options,
and the generated output.

Performing Compartmental Analysis
Fitting Data with In a single dose situation you can execute the fitting method
without entering any initial parameter values. The templates and
Kinetica - Single methods for fitting are categorized by the topics discussed below.
Dose
Route of Administration Whether you want to obtain a fit using first macro and then
micro constants or vice-versa.
There are four primary routes of administration:
• IV Bolus
• Extravascular
• IV Infusion
• Zero Order Input.
IV Bolus Kinetica provides TmaxCalc and CmaxCalc as output variables.

CmaxCalc corresponds to the IV extrapolated concentration at
t=0 and TmaxCalc=0. Lz always represents the smallest
disposition rate constant.
Extravascular This method fits data for all routes other than IV Bolus and IV
Infusion (e.g. oral administration, I.M, etc.). The general
condition for use is an input (or absorption) following a first
order, therefore Kinetica provides Ka as an output variable. You
can fit with or without lag-time. Kinetica also provides TmaxCalc
and CmaxCalc as output variables. These two parameters can be
different from the TmaxObserved and the CmaxObserved. Lz
always represents the smallest disposition rate constant.
IV Infusion The Infusion duration is known, and is an input variable.

Kinetica also provides TmaxCalc and CmaxCalc as output
variables. These two parameters can be different from the
TmaxObserved and the CmaxObserved. Lz always represents the
smallest disposition rate constant.

Zero Order Input This method is used when you have a kinetic profile with a zero
order input function that is not an IV Infusion (for example oral,
I.M administration, etc). The Input duration (equivalent to the
Infusion duration in the IV Infusion) is an output variable and is
then estimated by Kinetica. TmaxCalc and CmaxCalc are
provided as output variables. These two parameters can be
different from the TmaxObserved and the CmaxObserved. Lz
always represents the smallest disposition rate constant.
Macro or Micro Constants By using Macro constant methods, you obtain directly:
• A, alpha
• B, beta
• C, gamma
By using Micro constant methods, you obtain directly:
• Vc = the apparent volume of the central compartment
• Kel = elimination rate constant from the central compartment
• K12, K21 = elimination rate constants from the central

compartment to the superficial ( 2nd) compartment, from the
superficial compartment to the central compartment
respectively

compartment to the deep
( 3rd) compartment, from the deep peripheral compartment to
the central compartment respectively
Note Lz always represents the smallest disposition rate constant.

▲
Whenever you use one of the templates supplied for fitting, you
will always find a method called “Macro to Micro” after using a
model employing macro constants, and you will always find a
method called “Micro to Macro” after using a model employing

Micro constants. You can always obtain all the constants (macro
and micro) when using any fitting method.
Creating a Single Dose Except for the methods related to units, Kinetica needs three
Fitting Template methods in a Single Dose Fitting template.
The first method is the fitting method depending, on the method

and macro/micro constants. It allows you to obtain the following
pharmacokinetic parameters that come directly from fitting
(except for the macro or micro constants):
• TmaxCalc, CmaxCalc
• AUC, AUMC
• MRT, Lz.
The methods are listed in the following table.
Route of Macroconstants Microconstants

Administration
IV Bolus FitMacroIVBolus FitMicroIVBolus
IV Infusion FitMacroIVInf FitMicroIVInf
Extravascular FitMacroExtravascular FitMicroExtravascular
0 Order Input FitMacro0OrderInput FitMicro0OrderInput
The second method enables the conversion of macro to micro

constants or micro to macro constants. The two methods are
called MacroToMicro and MicroToMacro.
The third method is a method written in the Kinetica Basic

Language. The method is called PkExFitDerive (for the
extravascular route) or PKIVFitDerive (for all other routes).
The PKExFitDerive or PKIVFitDerive method enables you to

obtain additional PK parameters such as:
T1/2 = half-life

Tabs = Duration of absorption (for the extravascular method

only)
Vss = Apparent volume of distribution at steady-state
Vz = Apparent volume of distribution during the terminal phase

(Lz)
Cl = Total clearance.
The following example displays these three methods

(FitMacroExtravascular, MacroToMicro, and PkExFitDerive) in
the Methods view for a Single Dose Extravascular Macro
Constants template.
Note Methods are organized and executed sequentially in

Kinetica. ▲
Figure 9-1. Methods View for a Single Dose Extravascular Macro Constants template.

Fitting Data with For multiple dose, you can not execute the fitting method
without entering initial parameters. The templates and methods
Kinetica - Multiple for fitting contain only Micro constant methods (no Macro
Dose constant methods).
IV Bolus and In the sample view of the Dataset pane you must have three input
Extravascular columns ready for the fitting: time, concentration and dose. You
simply enter the quantity of dose in the cell (Dose column)
adjacent to the time the dose was administered.
Time Concentration Dose
0 100
0.5 47.5615
1 45.2419
1.5 43.0354
2 40.9365
3 37.0409
6 27.4406
9 20.3285
12 15.0597
18 8.26494
24 54.5359 100
24.5 51.8762
25 49.3461
25.5 46.9395
26 44.6502

Time Concentration Dose
27 40.4012
30 29.9299
33 22.1726
36 16.4259
42 9.01472
48 54.9474 100
48.5 52.2676
49 49.7184
IV Infusion In the sample view of the Dataset pane you must have four input
columns ready for the fitting: time, concentration, dose, and
infusion duration. You simply enter the duration of the infusion
in the cell (Infusion Duration column) adjacent to each dose you
entered previously.
Figure 9-2. Sample View – Dataset Pane

Micro and Macro When using the Multiple Dose templates you obtain the
Constants following micro constants:
• Vc = Apparent volume of the central compartment
• Kel = Elimination rate constant from the central

compartment
• Ka, Tlag (if extravascular route)

compartment to the superficial (2nd ) compartment, from the
superficial compartment to the central compartment
respectively

compartment to the deep peripheral (3rd) compartment, from
the deep peripheral compartment to the central compartment
respectively.
Macro constants are A, B, C and alpha, beta, and gamma. Alpha,

beta, and gamma are dose independent parameters, while A, B
and C are dose-dependent parameters. You are required to enter
the dose for macro constants calculation. The results of A, B, C
depend on the values for dose that you entered. For simplicity, we
suggest that you enter a value of one "1" for dose, to calculate A,
B, and C.
Creating a Multiple Dose Except for the methods concerning units, Kinetica needs three
Fitting Template methods in a Multiple Dose Fitting template. The first method is
the fitting method depending on the route. This first method in
the fitting template only enables you to obtain the
pharmacokinetic parameters which come directly from the fitting
as follows:
• Ka, tlag (for extravascular route)
• Vc, Kel
• K12, K21, K13, K31.
The names of the methods are the following:

• IV Bolus
• FitMultiMicroIVBolus
• IV Infusion
• FitMultiMicroIVInf
• Extravascular
• FitMultiMicroExtravascular.
The second method, MicroToMacro, enables the conversion of

micro constants to macro constants.
The third method, CalcThalf, was written in the Kinetica Basic

Language and is applicable to one, two, and three compartment
models. It enables you to obtain T1/2 alpha, T1/2 beta and T1/2
gamma.
The following example illustrates these three methods

(FitMultiMicroIVBolus, MicroToMacro, and
CalcThalf123comp) in the Methods view for a Multiple Dose IV
Bolus Micro Constants template:
Note Methods are organized and executed sequentially in

Kinetica. ▲

Figure 9-3. Methods View for a Multiple Dose IV Bolus Micro Constants

Available Models Kinetica includes one, two and three compartment Zero Order
Absorption (single dose only), Extravascular, IV Bolus and IV
Infusion models for single and multiple dose regimens. These
models are included in the library of hard-coded methods. In
addition, there are also some soft-coded methods written in
Kinetica Basic. You have the option to open these soft-coded
methods in the Basic Editor and modify them to meet your own
requirements.
The methods hard-coded in C++ are listed in the table below.
Note No models for Multiple dose macro constants are

included because they require a dose-independent
parameterization. ▲
Hard-Coded Method Name Function in Kinetica
FitMacro0orderinput Single Dose Zero Order Macro Constants
FitMacroExtravascular Single Dose Extravascular Macro

Constants
FitMacroIVBolus Single Dose IV Bolus Macro Constants
FitMacroIVInf Single Dose IV Infusion Macro

Constants
FitMicro0orderinput Single Dose Zero Order Micro Constants
FitMicroExtravascular Single Dose Extravascular Micro

Constants
FitMicroIVBolus Single Dose IV Bolus Micro Constants
FitMicroIVInf Single Dose IV Infusion Micro Constants
FitMultiMicroExtravascular Multiple Dose Extravascular Micro

Constants
FitMultiMicroIVBolus Multiple Dose IV Bolus Micro Constants

Hard-Coded Method Name Function in Kinetica
FitMultiMicroIVInf Multiple Dose IV Infusion Micro

Constants
FitMultiMicro Multiple Dose With Multiple Method

Micro Constants
Hard-Coded Models: IV The following models are hard-coded for IV bolus analysis:
Bolus Macro Constants
(1A) C = A ⋅ e − alpha ⋅t
(1B) C = A ⋅ e − alpha ⋅t + B ⋅ e − beta ⋅t
(1C) C = A ⋅ e − alpha ⋅t + B ⋅ e − beta ⋅t + C ⋅ e − gamma ⋅t

Hard-Coded Models: IV The following models are hard-coded for IV infusion analysis:
Infusion Macro Constants
T = infusion duration
(2A)
C t<T =
A
alpha ⋅ T
(
⋅ 1− e
− alpha ⋅ t
)
C t≥T =
A
alpha ⋅ T
( − alpha ⋅( t − T ) − e − alpha ⋅t )
⋅ e
(2B)
C =
A ⎛
⋅ ⎜1 − e
− alpha ⋅ t ⎞
⎟+
B
⋅⎛
⎜1 − e
− beta ⋅ t ⎞
⎟
t<T alpha ⋅ T ⎝ ⎠ beta ⋅ T ⎝ ⎠
C =
A ⎛
⋅ ⎜e
− alpha ⋅ ( t − T )
−e
− alpha ⋅ t ⎞
⎟+
B ⎛
⋅ ⎜e
− beta ⋅ ( t − T )
−e
− beta ⋅ t ⎞
⎟
t≥T alpha ⋅ T ⎝ ⎠ beta ⋅ T ⎝ ⎠
(2C)
⋅ (1 − e− alpha⋅t )+ ⋅ (1 − e−beta ⋅ t )+ ⋅ (1 − e−gamma⋅ t )

A B C
Ct <T =
alpha⋅ T beta ⋅ T gamma⋅ T
⋅ (e−alpha⋅( t −T ) − e−alpha⋅ t )+ ⋅ (e−beta ⋅( t −T ) − e− beta ⋅t )+ ⋅ (e−gamma⋅( t −T ) − e−gamma⋅t )

A B C
Ct ≥T =
alpha⋅ T beta ⋅ T gamma⋅ T
Hard-Coded Models: The following models are hard-coded for extravascular analysis:
Extravascular Macro
When (t<=lag), C = 0
Constants
tl = t - lag
(3A)
C = A ⋅
Ka
Ka − alpha
(
⋅ e − alpha ⋅ tl
− e − ka ⋅ tl )

(3B)
C = A ⋅
Ka
Ka − alpha
(
⋅ e − alpha ⋅ tl
)
− e − ka ⋅ tl + B ⋅
Ka
Ka − beta
⋅ e − beta ( ⋅ tl
− e − ka ⋅ tl )
(3C)
C=A⋅
Ka
( )
⋅ e − alpha ⋅ tl − e − ka ⋅ tl + B ⋅
Ka
( )
⋅ e − beta ⋅ tl − e − ka ⋅ tl + C ⋅
Ka
(
⋅ e − gamma ⋅ tl − e − ka ⋅ tl )
Ka − alpha Ka − beta Ka − gamma
Hard-Coded Models: IV When selecting one of the Micro constant templates in Kinetica,
Bolus Micro Constants we first compute the model using macro constants and then call a
MacroToMicro method that converts the results to micro
constants. This process is completely automatic. The two steps
are described below:
• STEP A - Compute macro constants
Use Equations 1A, 1B, or 1C.
• STEP B - Convert from macro to micro constants depending

on the number of compartments
(4) One compartment micro constants
Kel = Lz = alpha
Co = A
(5) Two compartment micro constants
Co = A + B
alpha ⋅ beta
Kel =
K 21
A ⋅ beta + B ⋅ alpha
K 21 =
Co
K12 = alpha + beta - (K21 + Kel)

(6) Three compartment micro constants
Co = A + B + C
a = alpha + beta + gamma
C ⋅ alpha + B ⋅ alpha + A ⋅ gamma + B ⋅ gamma + A ⋅ beta + C ⋅ beta

b=
− Co
C ⋅ alpha ⋅ beta + B ⋅ alpha ⋅ gamma + A ⋅ beta ⋅ gamma

c=
Co
−b− ( b2 − 4c)
K 31 =
2
K21 = -b - K31
alpha ⋅ beta ⋅ gamma

Kel =
K 21 ⋅ K 31
( beta ⋅ gamma + alpha ⋅ beta + alpha ⋅ gamma − K 21 ⋅ a − Kel ⋅ K 31 + K 221 )

K 12 =
(K − K )
31 21
K13 = a - (Kel + K12 + K21 + K31)
Hard-Coded Models: Zero When selecting one of the Micro constant templates in Kinetica,
Order and IV Infusion we first compute the model using macro constants and then call a
Micro Constants
• STEP A – Compute macro constants
Use Equation set (2).
• STEP B – Convert from macro to micro constants depending


Use Equations (4), (5), or (6).
Hard-Coded Models: When selecting one of the Micro constant templates in Kinetica
Extravascular Macro we first compute the model using macro constants and then call a
Constants
• STEP A – Compute macro constants
Use equations (3A), (3B), or (3C).
• STEP B – Convert from macro to micro constants depending

Use Equation (6).

IV Bolus Fitted Model - The table below catalogs the equations for PK parameters for the
Equations for PK IV Bolus fitted model.
Parameters
Parameter One Compartment Two Compartments Three Compartments
Vc Dose Dose Dose

Vc = Vc = Vc =
A A + B A + B + C
AUC A A B AUC =
A
+
B
+
C
AUC = AUC = + alpha beta gamma
alpha alpha beta
AUMC A A B A B C
AUMC = + +
AUMC = AUMC = 2 + alpha 2 beta 2 gamma 2
alpha 2 alpha beta 2
MRT AUMC
MRT =
AUC
T ln2 ln2 ln2

T1/ 2 alpha = T1/ 2 beta = T1/2gamma =
alpha beta gamma
Cl Dose
Cl =
AUC
V Vss = Cl ⋅ MRT
V Cl
Vz =
Lz

IV Infusion Fitted Model - The following table summarizes the equations for the PK
Equations for PK parameters of the IV infusion fitted model:
Parameters
Vc Dose Dose Dose

Vc = Vc = Vc =
A A + B A + B + C
AUC A A B A B C
AUC = AUC = + AUC = + +
alpha alpha beta alpha beta gamma
AUMC A A B A B C
AUMC = AUMC = + +
AUMC = 2 + alpha 2 beta 2 gamma 2
alpha 2 alpha beta 2
MRT AUMC
MRT =
AUC
T ln2 ln2 ln2

alpha beta gamma
Cl Dose
Cl =
AUC
V Vss = Cl ⋅ MRT
V Cl
Vz =
Lz

Extravascular Fitted The table below summarizes the equations for PK parameters for
Model - Equations for PK the extravascular fitted model.
Parameters
Vc Dose Dose Dose

Vc = Vc = Vc =
A A + B A + B + C
AUC Ka ⎛ 1 1 ⎞ ⎡ Ka ⎛ 1 1 ⎞⎤ ⎡ Ka ⎛ 1 1 ⎞⎤
AUC = A ⎜ − ⎟ AUC = ⎢ A ⎜ − ⎟⎥ AUC = ⎢ A ⎜ − ⎟⎥
Ka − alpha ⎝ alpha Ka ⎠ ⎣ Ka − alpha ⎝ alpha Ka ⎠⎦ ⎣ Ka − alpha ⎝ alpha Ka ⎠⎦
⎡ Ka ⎛ 1 1 ⎞⎤ ⎡ Ka ⎛ 1 1 ⎞⎤
+⎢ B ⎜ − ⎟⎥ +⎢ B ⎜ − ⎟⎥
⎝
⎣ Ka − beta beta Ka ⎠ ⎦ ⎣ Ka − beta ⎝ beta Ka ⎠⎦
⎡ Ka ⎛ 1 1 ⎞⎤
+⎢ C ⎜ − ⎟⎥
⎣ Ka − gamma ⎝ gamma Ka ⎠⎦
AUMC ⎡ Ka ⎛ 1 1 ⎞⎤ ⎡ Ka ⎛ 1 1 ⎞⎤ ⎡ Ka ⎛ 1 1 ⎞⎤
AUMC = ⎢A ⎜ 2 − ⎟⎥ AUMC = ⎢A ⎜ 2 − ⎟⎥ AUMC = ⎢A ⎜ 2 − 2 ⎟⎥
⎣ Ka − alpha ⎝ alpha Ka 2 ⎠ ⎦ ⎣ Ka − alpha ⎝ alpha Ka 2 ⎠ ⎦ ⎣ Ka − alpha ⎝ alpha Ka ⎠⎦
⎡ Ka ⎛ 1 1 ⎞⎤ ⎡ Ka ⎛ 1 1 ⎞⎤
+ ⎢B ⎜ 2 − 2 ⎟⎥ + ⎢B ⎜ 2 − ⎟
⎣ Ka − beta ⎝ beta Ka ⎠⎦ ⎝
⎣ Ka − beta beta Ka2 ⎠ ⎥⎦
⎡ Ka ⎛ 1 1 ⎞⎤
+ ⎢C ⎜ 2 − 2 ⎟⎥
⎣ Ka − gamma ⎝ gamma Ka ⎠⎦
MRT AUMC ⎛ 1 ⎞
MRT = − ⎜ lag + ⎟
AUC ⎝ Ka ⎠
T ln2 ln2 ln2

alpha beta gamma
Cl Dose
Cl =
AUC
V Vss = Cl ⋅ MRT
V Cl
Vz =
Lz

Equations for Fitting For fitting all cases of PK multiple dose data, Kinetica uses the
Multiple Dose Data principle of superposition by following these steps:
1. Calculating the concentrations (Ccalc) for each

administration in an independent manner by using the
equations computed for the single dose micro constant model
corresponding to each method (see the equations for single
dose micro constants, Hard-Coded Models: IV Bolus Micro
Constants and Hard-Coded Models: Zero Order and IV
Infusion Micro Constants in this chapter).
2. Adding the Ccalc computed values for each time.
3. Plotting the curve where Ccalc = f (t) to obtain the total

kinetic profile containing all the administrations.
4. Computing the fitting from this curve.

Selecting a Method You can select the hard-coded methods for fitting or simulation
in the Method Selection dialog. We call these method models
Model because they are specific methods for modeling data rather than
simple functions. The soft-coded methods are stored in text files
with the *.BAS extension and can be retrieved in the Method
Editor. When you choose a method from the Method Selection
dialog, you can view the associated input and output parameters
and a brief explanation of what the method computes.
To select a method model
1. Load Kinetica and open the appropriate file.
• Select Method from the Insert menu. The Method

Selection dialog appears. Choose a hard-coded or a soft-
coded method from the available lists.
• Create your own soft-coded model method by clicking

Method Editor in the Methods pane
Use Designer to create your method graphically by selecting

Designer then Standard from the Tools menu. For more
information, see the section, “Kinetica Designer” in the chapter,
“Working with Methods and Models.”

Initial Parameter The start values will affect the iterative procedure to converge to a
solution. Inadequate start information may result in convergence
Estimates to an unreliable point, where the final parameter values do not
provide the true optimum, but rather a “local” optimum.
You do not have to provide start values for a single-dose study,

however, you must enter some start values in the parameter cells
of the study or dataset group for multiple dose and steady state
datasets. These cells are automatically inserted if you choose a
hard-coded method, but you must create them if you insert a
soft-coded method. For single dose datasets you can enter your
own values, or use the Kinetica stripping algorithm (and in any
order you like). We recommend that you use the Kinetica
stripping algorithm. It requires no numerical entries to calculate
the initial estimates and tries to optimize the start points.

Stripping Algorithm The Stripping algorithm enables you to estimate the parameters
of one or two compartment linear models only (J.G. Wagner,
Fundamentals of Clinical Pharmacokinetics, Drug Intelligence
Pub. Inc. Hamilton, Illinois, 1975). The equations that define
the model are assumed to be polyexponentials. The number of
exponents is determined by the number of compartments.
The Stripping algorithm starts the calculations using a log-linear

regression on the observations pertaining to the terminal
elimination phase of the curve. Then the parameters of all phases
are calculated by recursive subtraction of the predicted values
from the ones observed in the initial portion of the curve.
The algorithm automatically estimates the parameters for any

possible combination of the number of points defining the
exponential kinetic processes. The final parameters retained are
the ones that give the minimal sum of squared differences
between the experimental and computed values.
If Stripping Fails When the stripping algorithm fails, #ERR appears in the initial
estimate spreadsheet cells and a message is written in the Dataset
Info view for each Dataset stripping failure ("Data not
compatible with the stripping assumption, enter some initial
values").
Stripping can fail for any of the following reasons:
• If the last point of the curve does not correspond to the

terminal phase, e.g. if the last point is around Cmax in an
extravascular administration
• If there are not enough points available to compute

(minimum number of points is 2 x number of compartments
in the most general cases, although there are some exceptions
to this rule)
• If a significant random noise is present in the data
• If the kinetics do not follow a multi-exponential model.

Weighting Schemes When you insert a method into a study, you can specify the
weight using the Options Setup dialog in the Methods view. The
default setting is a constant weight (=1) is. The available
weighting schemes are listed in the following table.
Label Weighting Scheme
1 Constant (default value)
Yobs 1/ Y observed
Yobs*Yobs 1/ Y observed2
Ycalc 1/ Y predicted
Ycalc*Ycalc 1/ Y predicted2
User-Defined User-defined (available for soft-coded

methods only)
User-Defined Weighting This option is available for soft-coded methods only. There are
two ways of performing user-defined weighting:
The first way requires a column in the sample view containing

the weighting values that will be assigned to each observation.
You must insert this column, enter the weight values for each
observation, and then reference the column in your soft-coded
method.
The second way uses the values calculated in your soft-coded

model as weighting. In this case, you do not need to insert a
column for weighting. The method will automatically generate
that column.

Minimization Kinetica, like many kinetic modeling programs, uses a modified

Gauss-Marquardt algorithm for minimization. Marquardt's
Algorithm method represents a compromise between the linearization
method and the steepest descent method and appears to combine
the best features of both while avoiding their most serious
limitations.
Marquardt's Principle Suppose we start from a certain point in the parameter space, ‘b’;
if the method of steepest descent is applied, a certain vector
direction, δg where g stands for gradient, is obtained from
movement away from the initial point. Due to attenuation in the
S (b) (S is the objective function to be minimized in b) contours
this may be the best local direction in which to move to attain
values of S(b) but may not be the best overall direction. However,
the best direction must be within 90° of δg or else S(b) will be
larger locally.
Marquardt found that for a number of practical problems to be

studied, the angle between δg and δt fell in the range 80° - 90°.
In other words, the two directions were almost at a right angle.
The Marquardt algorithm provides a method for interpolating
between the vector δg and δt and for obtaining a suitable step
size as well.
References for Further Reading Please consult the following references for more discussion of
Marquardt’s Principle.
Marquardt, D.W., 'An algorithm for least squares estimation of

nonlinear parameters', Journal of the society for Industrial and
Applied mathematics, 11, 431 441 (1963)
Press W.H, Teukolsky S.A, Vetterling W.T, and Flannery B.P,

“Numerical recipes in C, The Art of Scientific Computing”,
Second Edition, Cambridge University Press (1992)

Differential Equation Kinetica uses a numerical integration algorithm based on the

Runge-Kutta-Fehlberg method to compute the regression
Solver function values, when the structural model is described by a
system of differential equations [Forsythe G.E., Malcolm M.A.
and Moler C.B., Computer Methods for Mathematical
Computations, N.J., Prentice Hall Inc. 1977].
This is a 5th order method with variable step-size control.

Initially a step length satisfying a local error criterion is estimated,
then the 4th and 5th order Runge-Kutta approximation of the
solution are computed and used to estimate the local error. The
5th order estimation is used as the solution if, and only if, the
estimated error is less than a fixed tolerance level. If this is not the
case, the step size is reduced until the error criterion is satisfied.
Reference for Further Please consult the following reference for further discussion of the
Reading Runge-Kutta-Fehlberg algorithm:


Statistics and Kinetica generates detailed statistics for interpreting the model
selection and goodness of fit including: Objective Function,
Goodness of Fit Akaike & Schwartz Criteria, Standard Deviation (S.D.) &
Coefficient of Variation (%CV), Correlation Matrix and the
Residuals & Weighted Residuals.
Objective Function The objective function is computed as the sum of squares, where:
(Ycalc − Yobs) 2
∑ Weight
In Kinetica, the best fit is determined by the smallest objective

function found.
References for Further Press W.H, Teukolsky S.A, Vetterling W.T, and Flannery B.P,
Reading “Numerical recipes in C, The Art of Scientific Computing”,
The Akaike Criteria The Akaike criteria tries to identify the content of specific
parameter estimates by relating the coefficient of variation to all
the parameters required for the fitting. The Akaike criteria is
expressed as:
⎛ n 2⎞
Akaike = n ∗1n ⎜ ∑ Wi (Yobsi − Ycalci ) ⎟ + 2 p
⎝ i =1 ⎠
The Akaike value is dependent on the size of the data points and
the number of observations. In Kinetica the best model selection
is determined by the smallest Akaike value found.

The Schwartz Criteria The Schwartz criteria is defined as follows:
Schwartz = - Log likelihood + 1/2 Log N
where N = the number of data points
The best model selection is determined by the smallest Schwartz

value found.
Note It is always important to check the residual raw values

before assuming that the Akaike or Schwartz values are accepted
as the best fit indicator. ▲
References for Further Consult the following references for further discussion of the
Reading Akaike and Schwartz criteria:
Akaike H., “A New Look at Statistical Model Identification”,

IEEE Trans. Automat. Contr., 19: 716-723 (1973)
Akaike H., “An Information Criterion (AIC)”, Math Sci, 14: 5-9
(1976)
Standard Deviation and In Kinetica, Standard Deviation (S.D.) and Coefficient of

Coefficient of Variation Variation (%CV) are used as indicators for the goodness of fit.
The S.D. of the computed data can be typically defined as:
Σx 2 −
(Σx )2
sd =
Σ cn=1 (x i − x )
2
= n
n n
During a Kinetica analysis a warning message is displayed in a

message box and in the Dataset Info view for each dataset
analyzed if the calculated Coefficient of Variation (%CV) is
greater than 50 for any parameter. A second warning message is
generated if the calculated CV% is greater than 1000 for any
parameter.

The %CV of the computed data can be typically defined as:
%CV = SD / mean x 100
Reading "Numerical recipes in C, The Art of Scientific Computing",
Correlation Matrix In Kinetica, the correlation matrix provides an indication of the

degree of inter-dependency between the computed estimates of
the different parameters. In general, transforming the regression
problem into a format involving correlations is a good statistical
tool. It makes all the output values computed during the fitting
lie between the range -1 to 1. When the values are all of this order
the adverse effects of ‘rounding-off’ the error are minimized.
During a Kinetica analysis, a message is displayed in the Dataset

Info view for each dataset analyzed if the calculated correlation is
greater than 0.99 between two different parameters. This
indicates that the application has a strong assumption that you
are over-parameterized.
References for Further Draper N., and Smith H., “Applied Regression Analysis”, Second
Reading Edition, Wiley Interscience (1980)


Residuals and Weighted Residuals are widely used as an important marker to assess the
Residuals model selection and goodness of fit. A residual value is the
difference between the observed Y concentration and the
predicted Y concentration that is computed by Kinetica. Kinetica
recognizes these residuals with the notation Yobs and Ycalc
respectively. The resulting residual is the unexplained model
error. In a good fit circumstance this error should be randomly
distributed around the Ycalc mean.
Kinetica automatically outputs both the residuals and weighted

residuals after an analysis. These values are displayed in the
Dataset Info view for each dataset analyzed. In addition, you can
view a plot of the residuals by highlighting the Ycalc and
Residuals or Weighted Residuals columns, then clicking the
"Show one graph" or "Show all graphs" button.
Reading “Numerical recipes in C, The Art of Scientific Computing”,

PK Template PK templates enable you to study PK fitting and how it is applied

in Kinetica. Kinetica offers many different types of templates for
Examples PK fitting.
In order to understand how to use these templates, we supply a

description of each template type and a kdb file containing data.
This way you can try each analysis and understand how the
application operates before using your own data. Once you try
the example, you can open the empty template, cut and paste
your own data, and rerun the analysis.
The templates are listed in the following table:
Template Name Use in Kinetica
Macro0orderInput Single Dose Zero Order Input

Macro Constants
MacroExtravascular Single Dose Extravascular Macro

Constants
MacroIVBolus Single Dose IV Bolus Macro

Constants
MacroIVInfusion Single Dose IV Infusion Macro

Constants
Micro0orderInput Single Dose Zero Order Input

Micro Constants
MicroExtravascular Single Dose Extravascular Micro

Constants
MicroIVBolus Single Dose IV Bolus Micro

Constants
MicroIVInfusion Single Dose IV Infusion Micro

Constants
MultiMicroExtravascular Multiple Dose Extravascular Micro

Constants

Template Name Use in Kinetica
MultiMicroIVBolus Multiple Dose IV Bolus Micro

Constants
MultiMicroIVInf Multiple Dose IV Infusion Micro

Constants
MultiDoseMultiRoute Multiple Dose With Multiple

Administration Routes

Single Dose Zero This template enables you to perform a pharmacokinetic fitting
when you have data relative to Single Dose Zero Order Input
Order Input Macro with Macro Constants. There are no special conditions for using
Constants Template this template.
Inputs and Outputs Inputs are numeric fields and columns where you must enter data
so that Kinetica can successfully complete the analysis. Outputs
Study pane.
Dose – Amount of drug administered
• T = Time
• C = Concentration
add unity to the columns and assure that the program
understands and computes the correct final measurement units
required.
The other methods are explained in the following table:
FitMacro0orderInput Ccalc Computed

concentration values
Residuals Residuals
Weight Weight
Weighted Weighted Residuals

res.

Input Duration of the input

duration phase
A Coefficients in the sum

of exponentials
Alpha Exponent
B Coefficients in the sum

of exponentials
Beta Exponent
C Coefficients in the sum

of exponentials
Gamma Exponent
AUC Partial area under the

curve
AUMC Partial Area under the

moment curve
MRT Mean residence time
Lz Smallest (slowest)
disposition rate
constant
Cmax calc Calculated maximum

concentrate
Tmax calc Time where C=Cmax
MacroToMicro Vc Volume in the central

compartment
Kel Elimination rate

constant from central
compartment

K12 Transfer rate constant

from central
compartment to the
superficial
compartment

from superficial
compartment to the
central compartment

from central
compartment to the
deep peripheral
compartment

from deep peripheral
compartment to the
central compartment
PkIVFitDerive t1/2 alpha Elimination half-life of

Alpha
t1/2 beta Elimination half-life of

Beta
t1/2 gamma Elimination half-life of

Gamma
t1/2 Lz Elimination half-life

associated with the
terminal slope
t1/2 Kel Elimination half-life of

Kel

Vss Apparent volume of

distribution at steady
state
Vz Apparent volume of
distribution during the
terminal phase (Lz)
Cl Total clearance
Viewing an Example of Single A drug dose of 200,000 µg was administered orally. The
Dose Zero Order Input Macro concentration-time course was sampled from the plasma,
Constants Template expressed in µg/L and h respectively. A one-compartment model
with zero order absorption was used to analyze this example. This
example contains data for one dataset.
Note For this example we entered data into the template and
saved it as a .kdb file. If you open the corresponding file in the
Template subdirectory, you will not see any data. It is ready for
your own data. ▲
To view an example of the single-dose zero-order macro constants

template:
1. In Kinetica, select Open from the File menu. The Open a

Kinetica File dialog appears. By default, the program displays
the Data subdirectory.
2. Double click the Fitting directory, select the

Macro0orderInput.kdb file and click Open. The dataset
appears in the workspace, containing only the raw data that
we entered before sending you the application. You are ready
to run the analysis.

analysis. The results are plotted and displayed in the
workspace.

Modifying Options for the To modify options for the FitMacro0orderInput method:
FitMacro0orderInput Method
1. First, ensure that the number of compartments (Nb Comp)
you select is consistent.
3. Click Set in the Global Options column of the

FitMacro0orderInput row. The Options Setup dialog
appears.
4. Select from the following table:
Nb Comp Select one, two or three compartments
Weight Select one of the following weighting schemes:
Yobs 1/ Y observed
Yobs* Yobs 1/ Y observed2
Ycalc* Ycalc 1/ Y predicted2
Plot Curve Choose between Yes and No to plot automatic

graphs
Execute Choose between Fitting and Simulation. If you

choose Simulation you must enter the initial
parameter estimates in the parameter cells.
Modifying MacroToMicro To modify MacroToMicro options:

Options
1. Ensure that the number of compartments (Nb Comp) you
select is consistent.


MacroToMicro row. The Options Setup dialog appears.
4. Select from the following Nb Comp: One, two, or three

compartments.
Plotting the Residuals To plot the residuals:
1. Highlight the C and Residuals (or Weighted Residuals)

columns in the appropriate dataset in the Dataset pane, using
the mouse and the Ctrl key.
2. Click the Dataset Graph button. The residual plot is

displayed.
3. By default, Kinetica joins all points with a line. To suppress

the line, select the Style button in the graph window to
display the Style Property dialog. Deselect the Line option
and click OK.
Viewing Fitting Statistics To view statistics on the data fitting select the Dataset Info view
in the Dataset pane.
Single Dose This template enables you to perform a pharmacokinetic fitting

Extravascular Macro when you have data relative to Single Dose Extravascular with
Macro Constants. There are no special conditions for using this
Constants Template
template.

Study pane.
T = Time
C = Concentration
required. The other methods are explained in the following table.
Methods Column and Variable Outputs
FitMacroExtravascular Ka Absorption rate constant
Tlag Lag time
Note In Kinetica, the duration of absorption Tabs is calculated

as follows: Tabs = 5T½Ka. The absorption phase is considered
finished when time > 5T½Ka. ▲

Viewing an Example of A drug dose of 10µg was administered orally. The concentration-
Single Dose time course was sampled from the plasma. Units for time and
concentration are expressed in h and µg/L, respectively. A two-
Extravascular Macro
compartment model with first order absorption and lag-time was
Constants Template used to analyze this example. This example contains data for one
dataset.
Note For this example, we entered some data into the template
and saved it as a .kdb file. If you open the corresponding file in
the Template subdirectory, you will not see any data. It is ready
for your own data. ▲
To view the single dose extravascular macro constants template
1. Launch Kinetica.
2. Select Open from the File menu. The Open a Kinetica File
dialog appears. By default, the program displays the Data
subdirectory.
3. Double click the Fitting directory.
4. Select the MacroExtravascular.kdb file and click Open. The

dataset appears in the workspace, containing only the raw
data that we entered before sending you the application. You
are ready to run the analysis.

workspace.
Modifying MacroToMicro To modify MacroToMicro options first ensure that the number
options of compartments (Nb Comp) you select is consistent when you
modify method options, then follow the steps below.



compartments.
Plotting the Residuals To plot residuals:

2. Click the Dataset Graph button. The residual plot appears.
Viewing Statistics on the Fitting To view the statistics on the fitting select the Dataset Info view in
the Dataset pane.

Single Dose IV Bolus This template enables you to perform a pharmacokinetic fitting
when you have data relative to Single Dose IV Bolus with Macro
Macro Constants Constants. There are no special conditions for using this
Template template.
Study pane.
T = Time
C = Concentration
required.
Viewing an Example of A drug dose of 496 mg was administered by an IV bolus route.

Single Dose IV Bolus The concentration-time course was sampled from the plasma,
expressed in mg/L and min. respectively. A two-compartment
Macro Constants
model was used to analyze this example. This example contains
Template data for one dataset.
Note For this example we entered some data into the template
and saved it as a .kdb file. If you open the corresponding file in
the Template subdirectory, you will not see any data. It is ready
for your own data. ▲

To view the single dose IV bolus macro constants template
1. Launch Kinetica.
subdirectory.

MacroIVBolus.kdb file and click Open. The dataset appears
in the workspace, containing only the raw data that we
entered before sending you the application. You are ready to
run the analysis.

workspace.
Modifying FitMacroIVBolus To modify FitMacroIVBolusOptions first ensure that the number

Options of compartments (Nb Comp) you select is consistent when you
modify method options.

FitMacroIVBolus row. The Options Setup dialog appears.
3. Select from the following:
Yobs 1/ Y observed


graphs

Modifying MacroToMicro To modify MacroToMicro options, first ensure that the number


compartments.


Viewing Statistics on the Fitting To view statistics on the fitting select the Dataset Info view in the
Dataset pane.

Single Dose IV This template enables you to perform a pharmacokinetic fitting

when you have data relative to Single Dose IV Infusion with
Infusion Macro Macro Constants. There are no special conditions for using this
Constants Template template.
Study pane.
Infusion Duration – Duration of the drug infusion
T = Time
C = Concentration
required.
Viewing an Example of A drug dose of 1 mg was administered by an IV infusion method

Single Dose IV Infusion over a period of two hours. The concentration-time course was
sampled from the plasma, expressed in mg/Land h. respectively. A
Macro Constants
two-compartment model was used to analyze this example. This
Template example contains data for one dataset.
To view an example of the single dose IV infusion macro

constants template:

1. Launch Kinetica.
subdirectory.

MacroIVInfusion.kdb file and click Open. The dataset

workspace.
Modifying FitMacroIVInf Options To modify FitMacroIVInf options:

FitMacroIVInf row. The Options Setup dialog appears.
Yobs 1/ Y observed


graphs

Modifying MacroToMicro To modify MacroToMicro options, first ensure that the number


compartments.

Viewing Statistics on the Fitting To view the fitting statistics select the Dataset Info view in the
Dataset pane.

Single Dose Zero This template enables you to perform a pharmacokinetic fitting
when you have data relative to Single Dose Zero Order Input
Order Input Micro with Micro Constants. There are no special conditions for using
Constants Template this template.
Study pane.
T = Time
C = Concentration
required.
Viewing an Example of A drug dose of 1 mg was administered by a subcutaneous route.

Single Dose Zero Order The concentration-time course was sampled from the plasma,
expressed in mg/L and h respectively. A two-compartment model
Input Micro Constants
with a zero order input phase was used to analyze this example.
Template This example contains data for one dataset.
To view an example of the single dose zero order input micro

constants template
1. Launch Kinetica.

subdirectory.

Micro0OrderInput.kdb file and click Open. The dataset

workspace.
Modifying FitMicro0orderInput To modify FitMicro0orderInput options:

Options

FitMacro0OrderInput row. The Options Setup dialog
appears.
Yobs 1/ Y observed


graphs

Modifying MicroToMacro To modify MicroToMacro options, first ensure that the number


compartments.

View Statistics on the Fitting To view fitting statistics select the Dataset Info view in the
Dataset pane.

Single Dose This template enables you to perform a pharmacokinetic fitting

when you have data relative to Single Dose Extravascular with
Extravascular Micro Micro Constants. There are no special conditions for using this
Study pane.
T = Time
C = Concentration
required.
Viewing an Example of A drug dose of 10 µg was administered orally. The concentration-

Single Dose time course was sampled from the plasma, expressed in µg/L and
h respectively. A two-compartment model with first order
Extravascular Micro
absorption and lag time was used to analyze this example. This
Constants Template example contains data for one dataset.
To view an example of single dose extravascular micro constants

template
1. Launch Kinetica.

subdirectory.

MicroExtravascular.kdb file, and click Open. The dataset

workspace.
Modifying To modify FitMicroExtravascular options:

FitMicroExtravascular Options

FitMicroExtravascular row. The Options Setup dialog
appears.
Yobs 1/ Y observed


graphs

Modifying MicroToMacro To modify MicroToMacro options, first ensure that the number

MacroToMicro row.The Options Setup dialog appears.

compartments.


Viewing Statistics on the Fitting To view the fitting statistics select the Dataset Info view in the
Dataset pane.

Single Dose IV Bolus This template enables you to perform a pharmacokinetic fitting
when you have data relative to Single Dose IV Bolus with Micro
Micro Constants Constants. There are no special conditions for using this
Template template.
Study pane.
T = Time
C = Concentration
required.
Viewing an Example of A drug dose of 496 mg was administered by an IV bolus route.

Single Dose IV Bolus The concentration-time course was sampled from the plasma,
expressed in mg/L and min. respectively. A two-compartment
Micro Constants
model was used to analyze this example. This example contains
Template data for one dataset.
To view an example of single dose IV bolus micro constants

template
1. Launch Kinetica.

subdirectory.

MicroIVBolus.kdb file, and click Open. The dataset appears
in the workspace, containing only the raw data that we
entered before sending you the application. You are ready to
run the analysis.

workspace.
Modifying FitMicroIV Bolus To modify FitMicroIV Bolus options:

Options

FitMicroIVBolus row. The Options Setup dialog appears.
Yobs 1/ Y observed

graphs


options of compartments (Nb Comp) you select is consistent when you


compartments.

the Dataset pane.

Single Dose IV This template enables you to perform a pharmacokinetic fitting

when you have data relative to Single Dose IV Infusion with
Infusion Micro Micro Constants. There are no special conditions for using this
Study pane.
T = Time
C = Drug Concentration
required.

Viewing an Example of A drug dose of 785.7 nmol was administered by an IV infusion

Single Dose IV Infusion route. The concentration-time course was sampled from the
plasma, expressed in nmol/L and min. respectively. A three-
Micro Constants
compartment model was used to analyze this example. This
To view an example of single dose IV infusion micro constants

template:
1. Launch Kinetica.
dialog appears. By default, the program displays the
subdirectory “Data.”

MicroIVInfusion.kdb file, and click Open. The dataset

workspace.

Modifying FitMicroIVInf Options To modify FitMicroIVInf options:

FitMicroIVBolus row. The Options Setup dialog appears.
Yobs 1/ Y observed

graphs




compartments.

the Dataset pane.

Multiple Dose This template enables you to perform a pharmacokinetic fitting

when you have data relative to Multiple Dose Extravascular with
Extravascular Micro Micro Constants. There are no special conditions for using this
Inputs and Out puts Inputs are numeric fields and columns where you must enter data
Study pane.
Ka – Initial parameter estimate
Vc – Initial parameter estimate
Kel – Initial parameter estimate
T – Time
C – Drug Concentration
required.

Viewing an Example of A drug dose of 10 µg was administered at 0, 4, 8, and 16h; 20 µg

Multiple Dose at 22, 28, 34, 44, 54, 66, and 74h; and 40 µg at 86 and 98h. The
concentration-time course was sampled from the plasma,
Extravascular Micro
expressed in µg/L and h respectively. A one-compartment model
Constants Template with first order absorption and no lag time was used to analyze
this example. This example contains data for one dataset.
To view an example of multiple dose extravascular micro

constants template
1. Launch Kinetica.
subdirectory.

MultiMicroExtravascular.kdb file, and click Open. The
4. In the Study All Variables view, enter some initial estimates

for the analysis. For this example, you can enter the following
values:
Ka = 0.5
Vc = 10
Kel = 0.1.

analysis. The results are plotted and displayed in the Gallery.

Changing To change the FitMultiMicroExtravascular options:

FitMultiMicroExtravascular
Options

FitMultiMicroExtravascular row. The Options Setup dialog
appears.
Use Lag Select Yes or No to compute lag time

Time
Yobs 1/ Y observed

graphs




compartments.

the Dataset pane.

Multiple Dose IV This template enables you to perform a pharmacokinetic fitting

when you have data relative to Multiple Dose IV Bolus with
Bolus Micro Micro Constants. There are no special conditions for using this
Study pane.
T – Time
required. The other methods are explained as follows:
FitMultiMicroIV Ccalc Computed concentration

Bolus values
Residuals Residuals
Weight Weight


Res.
Vc Volume in the central

compartment
Kel Elimination rate constant

from central compartment
K12 Transfer rate constant from

central compartment to the
superficial compartment

superficial compartment to
the central compartment

deep peripheral compartment

deep peripheral compartment
to the central
compartment
MicroToMacro A Coefficients in the sum of

exponentials
Alpha Exponent
B Coefficients in the sum of

exponentials
Beta Exponent
C Coefficients in the sum of

exponentials
Gamma Exponent

CalcThalf (1,2,3 t1/2 alpha Elimination half-life of Alpha

comp)
t1/2 beta Elimination half-life of Beta
t1/2 Elimination half-life of

gamma Gamma
Viewing an Example of A drug dose of 100 mg was administered at 0, 24, and 48h by an
Multiple Dose IV Bolus IV Bolus route. The concentration-time course was sampled from
the plasma, expresed in ng/mL and h respectively. A one-
Micro Constants
compartment model was used to analyze this example. This
To view an example of multiple dose IV bolus micro constants

template
1. Launch Kinetica.
2. Select Open from the File menu.The Open a Kinetica File

subdirectory.

MultiMicroIVBolus.kdbdirectory, and click Open. The
4. In the Study All Variables view, enter some initial estimates

for the analysis. In this example, you can enter the following
values:
Vc = 1
Kel = 0.2.


analysis. The results are plotted and displayed in the Gallery.
Changing FitMultiMicroIVBolus To change FitMultiMicroIVBolus options:

Options

FitMultiIVBolus row. The Options Setup dialog appears.
Yobs 1/ Y observed

graphs




compartments.

the Dataset pane.

Multiple Dose IV This template enables you to perform a pharmacokinetic fitting

when you have data relative to Multiple Dose IV Infusion with
Infusion Micro Micro constants. There are no special conditions for using this
Study pane.
K12 – Initial parameter estimate
K21 – Initial parameter estimate
Data input (user-entered dataset column field values):
T – Time
required. The other methods are described in the following table.

FitMultiMicroIVInf Ccalc Computed

Residuals Residuals
Weight Weight

Res.
Vc Volume in the central

compartment
Kel Elimination rate

constant from central
compartment

from central
compartment to the

from superficial
compartment to the
central compartment

from central
compartment to the
deep peripheral
compartment

from deep peripheral
compartment to the
central compartment
MicroToMacro A Coefficients in the sum

of exponentials

Alpha Exponent
B Coefficients in the sum

of exponentials
Beta Exponent
C Coefficients in the sum

of exponentials
Gamma Exponent
CalcThalf (1,2,3 t1/2 alpha Elimination half-life of

comp) Alpha
t1/2 beta Elimination half-life of

Beta
t1/2 gamma Elimination half-life of

Gamma
Viewing an Example of A drug dose of 177 mg was administered at 0, 24,08 and 48,08 h
Multiple Dose IV Infusion by an IV infusion lasting one hour. Likewise, a dose of 175,3 mg
was administered at 1h by an IV infusion lasting three hours.
Micro Constants
Another dose of 175,2 mg was administered at 25,08 and 49,08h
Template by an IV infusion lasting three hours. The concentration-time
course was sampled from the plasma, expressed in mg/L and h
respectively. A two-compartment model was used to analyze this
example. This example contains data for one dataset.
To view an example of multiple dose IV infusion micro constants

template
1. Launch Kinetica.
subdirectory.


MultiMicroIVInfusion.kdb file, and click Open. The dataset
4. In the Study All Variables View, enter some initial estimates

values:
Vc = 5
Kel = 0.5
K12 = 0.5
K21 = 0.1

analysis. The results are plotted and the respective plot is
generated.
Changing FitMultiMicroIVInf To change FitMultiMicroIVInf options:

Options

FitMultiMicroIVInf row. The Options Setup dialog appears.
Yobs 1/ Y observed


graphs



compartments.


the Dataset pane.

Multiple Dose Multi This template enables you to perform a pharmacokinetic fitting
when you have data relative to multiple dose and multiple
Route Template method with micro constants. There are no special conditions for
using this template. This template contains two views:
Plasma – contains columns for Ccalc, Residuals, Weight,

Weighted Res.
Administration – contains columns for information relative to the

administration (i.e. time, dose, method and infusion duration).
Study pane.
Dose for Macro Constant – Dose which should always be equal

to 1 (used only for obtaining macro constants, it is not the
administered dose)
T – Time
Admin Time – Time of drug administration
Admin Dose – Amount of drug administered
Admin Route – Choose to identify the administration method (1

= Extravascular, 2 = IV infusion, 3 = IV Bolus)
Infusion Duration – Duration of drug infusion

required.
The other methods are described in the following table.
FitMultiMicro Ccalc Computed concentration values
Residuals Residuals
Weight Weight

Res.
Ka Absorption rate constant (if

there is an oral administration)
Tlag Lag time
F Bioavailability
Volume Volume of distribution
Kel Elimination rate constant from

central compartment


superficial compartment to the
central compartment

central compartment to the deep
peripheral compartment

K31 Transfer rate constant from deep

peripheral compartment to the
central compartment
MicroToMacro A Coefficients in the sum of

exponentials
Alpha Exponent
B Coefficients in the sum of

exponentials
Beta Exponent
C Coefficients in the sum of

exponentials
Gamma Exponent
CalcThalf t1/2 alpha Elimination half-life of Alpha

(1,2,3 comp)
t1/2 beta Elimination half-life of Beta
t1/2 Elimination half-life of Gamma

gamma

Viewing an Example of A drug dose of 0.25 mg was administered by an IV bolus route.

Multiple Dose Multiple At 2h a dose of 1 mg is administered by an IV infusion over a
period of six hours. The concentration-time course was sampled
Method Micro Constants
from the plasma, expressed in mg/L and h respectively. Two-
Template compartment model was used to analyze this example. This
example contains data for one dataset.
To view an example of multiple dose multiple method micro

constants template
1. Launch Kinetica.
subdirectory.

MultiDoseMultiRoute.kdb file, and click Open. The dataset
4. In the Study All Variables View, enter some initial estimates

values:
Volume = 1
Kel = 0.5
K12 = 0.5
K21 = 0.25.

generated.

Changing FitMultiMicro Options To change FitMultiMicro options:

FitMultiMicro row. The Options Setup dialog appears.
Yobs 1/ Y observed

graphs




compartments.

the Dataset pane.

Performing PD Kinetica enables you to complete single dose pharmacodynamic

(PD) analysis with direct models or link models.
Analysis
General PD Template Several models have been developed to link the effect to drug
concentration or drug doses when the drug-induced response is
generated by a simple or multiple receptor activation. These
models are independent of time and describe the balanced
relationship between the concentrations and the effects.
The standard library used within Kinetica contains six different

models as described below.
Linear Model The linear model is proportional to concentration.
We compute:
E = S Ce + E0
where:
E = Effect variable
E0 = Baseline effect
S = Slope of the line relating the effect to the concentration
Ce = Concentration to which the effect is related
Log-Linear Model For the log-linear model we compute:
E = S log (Ce) + E0
where:
E = Effect variable
S = Slope of the line relating the effect to the concentration

Ordinary Emax Model We compute:
Ce
E = E 0 + E max⋅
Ce + EC50
where:
E = Effect variable
Emax = Maximum drug induced effect
EC50 = Plasma concentration at 50% of maximal effect
A graphical representation of the Ordinary Emax model is shown

below, where E0 is 0, Emax is 100, and EC50 is 20.
100
90
80
70
60
Effect (%)
50
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
Concentration (ng/m L)
Figure 9-4. Ordinary Emax Model with E0=0, Emax=100 and

EC50=20

Ordinary Inhibition Emax Model We compute:
Ce
E = E 0 − E max⋅
Ce + EC50
where:
E = Effect variable
A graphical representation of the Ordinary Emax model is shown

below, where E0 is 100, Emax is 100, and EC50 is 20.
100
90
80
70
60
Effect (%)
50
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
Figure 9-5. Ordinary Inhibition Emax Model with E0=100,

Emax=100 and EC50=20

Sigmoid Emax Model (Hill) We compute the Hill equation:
C ep
E = E 0 + E max⋅
Cep + EC50 p
where:
E = Effect variable
n = Sigmoidicity factor (Hill exponent)
100
90
80
70
60
Effect (%)
50
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
Figure 9-6. Graph of a Sigmoidal Emax Model

Sigmoid Inhibition Emax Model We compute the Hill equation:

(Hill)
C ep
E = E 0 − E max⋅
Cep + EC50 p
where:
E = Effect variable
n = Sigmoidicity factor (Hill exponent)
100
90
80
70
60
Effect (%)
50
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
Figure 9-7. Graph of a Sigmoidal Inhibition Emax Model
Kinetica provides one template that covers all of these

pharmacodynamic models. You can choose a specific model from
the options for the method called FitDynamic. This template is

available for all routesof administration (IV Bolus, IV Infusion,

and Extravascular).
Inputs Required Inputs are numeric fields and columns where you must enter data
so that Kinetica can successfully complete the analysis. The
following input and information can be found in the Study Info
worksheet in the Study pane.
S – Slope of the line relating the effect to the concentration
Emax – Maximum drug induced effect
EC50 – Plasma concentration at 50% of maximal effect
N – Hill exponent (sigmoidicity factor)
E0 – Baseline estimate
Note You only need to enter the estimates that are specific to
the general model you have selected. ▲
Cp – Drug concentration
Effect – Effect
Methods The Set Column Unit method is used to add unity to the
columns and assure that the program understands and inserts the
correct final measurement units required.
FitDynamic EffectCalc Calculated effect
Residuals Residuals
Weight Weight

Weighted Weighted residuals

Res
S Slope
Emax Maximum drug induced effect
EC50 Plasma concentration at 50% of

maximal effect
E0 E0 = Baseline effect (the output

variable which appears on the
screen depends on the selected
model)

Viewing an Example of In this example, a drug was given to a patient. Plasma

the General PD Template concentration (Cp) and effect observations were obtained at
steady state. A baseline effect E0 (E0=175) was observed with the
absence of a drug. Increased plasma concentration of the drug
(mg/L) decreased blood pressure (effect). The Emax inhibition
model with E0 equal to 175 was used to analyze this example.
This example contains data for one dataset.
To view an example of the general PD template
1. Select Open from the Kinetica File menu. The Open a

Kinetica File dialog appears. By default, the program displays
the Data subdirectory.
2. Double click the Fitting directory, select the General

Dynamics.kdb file, and click Open. The dataset appears in
the workspace, containing only the raw data that we entered
before sending you the application. You are ready to run the
analysis.
Figure 9-8. Dataset view (Plasma view)
3. Enter some initial estimates for the analysis in the All

Variables view (Study pane). For this example, you can enter
the following values:
Emax = 35
EC50 = 120
E0 = 175

4. Before running the analysis, examine a graph of the Cp versus

Effect values. Click the Dataset Graph button. The following
graph is displayed:
Figure 9-9. Graph Depicting Cp versus Effect Values

generated.
Figure 9-10. Graph Depicting Calculated Results of Analysis

Note If you have multiple datasets when you try your analyses,
you can select Calculate All from the toolbar. The results for all
datasets will be calculated in batch mode and displayed in the
Gallery feature. ▲
Exploring the Data with the For this example, select the Cp, Effect, and Weighted Res
Graphical Tools columns, then select the Dataset Graph item found in the Dataset
pane to view the results.
Exporting the Results Now that the analysis is complete, you can export the results to
Microsoft Word or Excel.
1. Load Excel and then select the columns or rows you want to
export from Kinetica.
2. Select Assistants then Export from the Tools menu.
3. Switch the view to Excel to view the data.
Changing the Fit Dynamic To change the fit dynamic options:

Options
2. Click Set in the Global Options column of the Fit Dynamic

row. The Options Setup dialog appears.
PD model Choose one of the following PD models:
Linear
Log-Linear
Emax

Emax Inhibition
Hill
Hill Inhibition
E0 is Choose one of the following:
User-defined Enter the baseline value E0 in

constant the group (even it is an output
variable)
Model If the baseline is not constant

parameter and varies then choose this
option, Kinetica will fit E0.
Yobs 1/ Y observed

graphs


Performing PK/PD The pharmacokinetic/pharmacodynamic (PK/PD) model used in

Kinetica is the model proposed by Sheiner et al. (1979). This
Analysis model can be viewed as the combination of three different
models: pharmacokinetic, link, and effect. The schema is shown
below.
Effect Model Pharmacokinetic Model
K 12
K 1e
Effect Comp. Central Comp. Periph. Comp.
Link Model
K 21
K e0 K el
Figure 9-11. PK/PD schematic
The PK model can be defined using the classical compartment

theory. In order to establish a relationship between the drug
concentrations in the effect site (Ce) which is usually unknown,
and the effect, we need to define a model. The latter enables us to
compute the drug concentration in the effect site from the
measured drug concentration in the central compartment. This
particular model is called the link model and can be defined as
follows:
K e0 Ce Cp
Effect Comp. Central Comp.
Figure 9-12. Link model schematic
Corresponding to:

dCe
= K1e ⋅ Cp − K e 0 ⋅ Ce
dt
where:
Ce – Drug concentration in the effect compartment
Cp – Drug concentration in the central compartment.
The effect site is considered as an additional compartment linked

to the plasma compartment by a first order process (rate K1e). It is
assumed that only a negligible mass of drug reaches this site.
Therefore, the kinetics of the drug is completely unaffected by the
presence of this hypothetical compartment. Drug removal is then
characterized by Ke0, where:
Ke0 – First order rate constant which characterizes the temporal

aspects of equilibration between plasma concentration and effect.
At the steady state, we have:
K
Cp = Ce ⋅
e 0
K 1e
If Ke0 is great, the Ce profile is parallel to the Cp profile.
In Kinetica, the PD equations used to fit a PD model are the

following three hard-coded methods:
FitPK/PD_Extravascular (for the extravascular route)
FitPK/PD_IVB (for the IV bolus route)
FitPK/PD_IVInf (for the IV infusion route).
The equations used in the above methods are described below:

First Order Absorption The expression for first order absorption is given as:
⎡ n
Cii ⋅ Ka ⎤
⎢ n ∑ ⎥
Ce(t ) = K ie ⎢∑
Cii ⋅ Ka
( )
⋅ e − Li⋅t − e − K e 0 ⋅t − i =1
Ka − Li
(
⋅ e − Ka⋅t − e − K e 0 ⋅t )⎥
⎢ i =1 (Ka − Li ) ⋅ (K e 0 − Li ) (K e0 − Ka ) ⎥
⎢⎣ ⎥⎦
Zero Order Absorption IV Bolus
⎡ n ⎤
Ce(t ) = K ie ⎢∑
Cii
(
⋅ e − Li⋅t − e − K e 0 ⋅t ⎥ )
⎣ i =1 ⋅ (K e 0 − Li ) ⎦
IV Infusion (during the perfusion):
n
Cii ⎡ 1 e − K e 0 ⋅t K e 0 ⋅ e − Li ⋅t ⎤
Ce(t ) = ∑ ⋅⎢ + − ⎥
i =1 T ⎣ Li K eo − Li Li ⋅ (K e 0 − Li ) ⎦
IV Infusion (post perfusion): The expression for IV Infusion is:
Ce(t ) = ∑
n
⋅⎢
(
Cii ⎡ K e 0 ⋅ 1 − e Li⋅t
⋅ e
)(
− Li ⋅(t −T )
−e )
− K e 0 ⋅( t − T ) ⎛1
⎜
+⎜ +
e − K e 0 ⋅T
−
K e 0 ⋅ e − Li⋅T ⎞ − K e 0 ⋅(t −T ) ⎤
⎟⋅e
⎟ ⎥
i =1 T ⎢⎣ Li ⋅ (K e 0 − Li ) ⎝ Li K e 0 − Li Li ⋅ ( K e 0 − Li ) ⎠ ⎥⎦
where:
Ce (t) = Drug concentration in the effect compartment
Cii = Coefficients in the sum of exponentials (A, B or C)
Li = Exponents (alpha, beta or gamma)
Ka = Absorption rate constant
Ke0 = Rate constant for drug removed from the effect

compartment

Generally, in PK/PD templates, there are two views:
• PK view: to fit PK data
• PD view: to fit PD data with PK parameters.
The principle advantage of this method (to fit PK and PD

separately) is that different weights can be attributed for PK and
PD fitting. The same weights are not always applicable to PK and
PD data.
Note The time corresponding to the plasma concentration can

be different from the time corresponding to the effect. ▲

PK/PD Extravascular The subsections below discuss the application of the PK/PD
Extravascular template.
Template
Inputs Required Inputs are numeric fields and columns where you must enter data
Ke0 – Rate constant for drug removal from the effect

compartment
S – Slope of the line relating the effect to the concentration
Data input (user-entered dataset column field values) in the PK

view:
T(Cp) – Time
Data input (user-entered dataset column field values) in the PD

view:
T (effect) – Effect time
Effect – Drug effect
understands and inserts the correct final measurement units
required.
The other methods are explained in the following table.
FitMacroExtravascular CpCalc Computed


Residuals Residuals
Weight Weight

Res.
Ka Absorption rate
constant
lag Lag time
A Coefficient in the
sum of exponentials
Alpha Exponent
B Coefficient in the
sum of exponentials
Beta Exponent
C Coefficient in the
sum of exponentials
Gamma Exponent
AUC Partial area under the

curve
AUMC Partial area under the

moment curve
disposition rate
constant
Cmax calc Extrapolated

concentration at 0

Tmax calc Extrapolated time at

0
FitPK/PD_Extravascular Ce Effect concentration
Effectcalc Computed
Residuals Residuals
Weight Weight

Res.
Ke0 Rate constant for

drug removal from
the effect
compartment
S Slope of the line

relating the effect to
the concentration
Emax Maximum drug

induced effect
EC50 Plasma concentration

at 50% of maximal
effect
n Hill exponent
(sigmoidicity factor)
E0 Baseline estimate

Viewing an Example of In this example, 200 µg of a drug was administered orally. The
PK/PD Extravascular concentration-time course was sampled from the plasma,
expressed in µg/L and h respectively. To fit PK data, a one-
Template
compartment model with no lag time was used. To fit PD data, a
linear model with E0=0 was used.
To view an example of the PK/PD extravascular template
1. Launch Kinetica.
subdirectory.
3. Double click the Fitting directory, select the PK/PD

Extravascular.kdb file, and click Open. The dataset appears in
the workspace.
Figure 9-13. Dataset view (PK view)
Note PK worksheets always contain input columns T and

C. ▲

Figure 9-14. Dataset view (PD view)
Note PD worksheets always contain input columns

T(effect) and Effect. ▲
4. In the All Variables view of the Study pane, enter some initial
estimates for the analysis. In this example, you can enter the
following values:
Ke0 = 0.18
S=1
5. Before running the analysis, examine a graph of the T(Cp)

versus Cp values.
6. Click the Dataset Graph button. The following graph

appears:

Figure 9-15. Dataset Graph Depicting T(Cp) versus Cp

values
7. Now plot a graph of the T(effect) versus Effect values. Select

the T(effect) and Effect columns from the PD view.
8. Click the Dataset Graph button. The following graph

appears:
Figure 9-16. Dataset Graph Depicting T(effect) versus Effect

values


analysis. The results are plotted and two graphs are generated.
Figure 9-17. Graph of PK Fitting
Figure 9-18. Graph of PD Fitting
you can select the Calculate All button found on the toolbar. The
results for all datasets will be calculated in batch mode and
displayed in the groups. You can scroll through the datasets to see
the results for different subjects. ▲

Exploring the Data with the In this case we will plot a hysteresis graph after the PK fitting,
Graphical Tools and then the collapsed hysteresis graph after the PD fitting.
1. Select Select Dataset Graph from the View menu. Select 1

from the Dataset list, PK.CpCalc from the Column X list,
and PD.Effect from the Column Y list, then click OK. The
hysteresis graph after PK fitting is displayed.
2. Select Select Dataset Graph from the View menu again. This
time select 1 from the Dataset list, PD.Effectcalc from the
Column X list, and PD.Ce from the Column Y list, then click
OK. The collapsed hysteresis graph after the PD fitting is
displayed.
Figure 9-19. Hysteresis Graph Generated after the PK Fitting

before the PD fitting

Figure 9-20. Collapsed Hysteresis Graph Generated after the

PD fitting
Note You can change the graph scaling to better view the
collapse of the hysteresis plot. For more information, see the
chapter, “Working with Graphs.” ▲

Changing To change FitMacroExtravascular options, first ensure that the

FitMacroExtravascular Options number of compartments (Nb Comp) you select is consistent
when you modify method options.

FitMacroExtravascular row. The Options Setup dialog
appears.
Nb Comp Choose one, two, or three compartments
Use Lag Choose between Yes and No to compute lag

Time time
Yobs 1/ Y observed

graphs


Changing To change FitPK/PD_Extravascular options:

FitPK/PD_Extravascular Options

FitPK/PD_Extravascular row. The Options Setup dialog
appears.
Nb Comp Choose one, two or three compartments
Linear
Log-Linear
Emax
Emax Inhibition
Hill
Hill Inhibition

variable)

Yobs 1/ Y observed


graphs

choose Simulation, you must enter the initial

PK/PD IV Bolus The subsections below describe the PK/PD IV Bolus template.
Template
Inputs Required Inputs are numeric fields where you must enter data so that
Kinetica can successfully complete the analysis. The following
input and information can be found in the Study Info worksheet
in the Study pane.
Dose – Dose administered
Ke0 – Rate constant for drug removal from the effect

compartment
Emax – Maximum drug induced effect
EC50 – Plasma concentration at 50% of maximal effect
E0 – Baseline estimate.
Data input (user-entered dataset column field values) in PK view:
T (Cp) – Time
Cp – Drug Concentration
Data input (user-entered dataset column field values) in PD view:
T(effect) – Effect time
required. The remaining methods are described in the following
table.

FitMacroIVBolus CpCalc Computed concentration

values
Residuals Residuals
Weight Weight

Res.
A Coefficient in the sum of

exponentials
Alpha Exponent
B Coefficient in the sum of

exponentials
Beta Exponent
C Coefficient in the sum of

exponentials
Gamma Exponent
AUC Partial area under the curve

moment curve
disposition rate constant
Cmax calc Extrapolated concentration

at 0
Tmax calc Extrapolated time at 0
FitPK/PD_IVB Ce Effect concentration

Effectcalc Computed concentration

values
Residuals Residuals
Weight Weight

Res.
Ke0 Rate constant for drug

removed from the effect
compartment
S Slope of the line relating

the effect to the
concentration
Emax Maximum drug induced

effect
EC50 Plasma concentration at

50% of maximal effect
n Hill exponent
(sigmoidicity factor)
E0 Baseline estimate.

Viewing an Example of A drug dose of 50 mg was administered by an IV Bolus route.

PK/PD IV Bolus Template The concentration-time course was sampled from the plasma,
expressed in mg/L and h respectively. An Emax inhibitive model
was used to fit PK data.
To view an example of the PK/PD IV Bolus template:
1. Launch Kinetica.
subdirectory.
3. Double click the Fitting directory, select the PKPD IV

Bolus.kdb file, and click Open. The dataset appears in the
workspace.
Figure 9-21. Dataset group (PK view)

Figure 9-22. Dataset group (PD view)

Ke0 = 1
Emax = 100
EC50 = 10
E0 = 100
5. Before running the analysis, examine a graph of the T(Cp)

versus Cp values. Click the Dataset Graph button. The
following graph appears:

Figure 9-23. Graph Depicting T(Cp) versus Cp values

the T(effect) and Effect columns from the PD view. Click the
Dataset Graph button found on the toolbar. The following
graph appears:
Figure 9-24. Graph Depicting the T(effect) versus Effect

values

analysis. The results are plotted and two graphs are generated.

Figure 9-25. Graph of PK Fitting
Figure 9-26. Graph of PD Fitting
Note If you have multiple datasets, when you try your analyses
you can click the Calculate All button from the toolbar. The
results for all datasets are calculated in batch mode and displayed
in the Graph Gallery. You can scroll through the datasets to see

Changing FitMacroIVBolus To change FitMacroIVBolus options, first ensure that the

Options number of compartments (Nb Comp) you select is consistent
when you modify method options.
2. Click Set in the Global Options column of the Fit

MacroIVBolus row. The Options Setup dialog appears.
Yobs 1/ Y observed

graphs


Changing FitPK/PD_IVB Options To change FitPK/PD_IVB options:

FitPK/PD_IVB row. The Options Setup dialog appears.
Linear
Log-Linear
Emax
Emax Inhibition
Hill
Hill Inhibition

variable)


Yobs 1/ Y observed

graphs


PK/PD IV Infusion The subsections below describe the PK/PD IV Infusion template.
Template
Inputs required Inputs are numeric fields and columns where you must enter data
Dose – Dose administered
Infusion Duration – Duration of drug infusion
Ke0 – Link constant between the central and effect

compartments
S – Slope of the line relating the effect

to the concentration
E0 – Baseline estimate
Data input (user-entered dataset column field values) in the PK

view:
T(Cp) – Time
Data input (user-entered dataset column field values) in the PD

view:
T (effect) – Effect time

required.
FitMacroIVInf CpCalc Computed concentration

values
Residuals Residuals
Weight Weight

Res.
A Coefficient in the sum of

exponentials
Alpha Exponent
B Coefficient in the sum of

exponentials
Beta Exponent
C Coefficient in the sum of

exponentials
Gamma Exponent
AUC Partial area under the curve

moment curve
disposition rate constant

Cmax calc Extrapolated concentration

at 0
Tmax calc Extrapolated time at 0
FitPK/PD_IVInf Ce Effect concentration
Effectcalc Computed concentration

values
Residuals Residuals
Weight Weight

Res.
Ke0 Rate constant for drug

removed from the effect
compartment
S Slope of the line relating the

effect to the concentration
Emax Maximum drug induced

effect
EC50 Plasma concentration at

50% of maximal effect
n Hill exponent (sigmoidicity

factor)
E0 Baseline estimate

Viewing an Example of In this example, one mg of a drug was administered with an

PK/PD IV Infusion infusion duration of two hours. The concentration-time course
was sampled from the plasma, expressed in mg/L and h
Template
respectively. To fit PK data, a two-compartment model was used.
To fit PD data, a linear model with a baseline E0=0 was used.
To view an example of the PK/PD IV infusion template
1. Launch Kinetica.
subdirectory.
3. Double click the Fitting directory, select the PKPD IV

Infusion.kdb file, and click Open. The dataset appears in the
workspace.
Figure 9-27. Dataset View (PK view)

Figure 9-28. Dataset View (PD view)

Ke0 = 2
S = 100
E0 = 0
5. Before running the analysis, look at a graph of the T(Cp)

versus Cp values. Click the Dataset Graph button. The
following graph is displayed:
Figure 9-29. Graph Depicting T(Cp) versus Cp Values


the T(effect) and Effect columns from the PD view. Click the
Dataset Graph button found on the toolbar. The following
graph appears:
Figure 9-30. Graph Depicting T(effect) versus Effect Values

analysis. The results are plotted and two graphs are generated:
Figure 9-31. PK Graph

Figure 9-32. PD Graph
you can select the Calculate All button found on the toolbar. The
results for all datasets will be calculated in batch mode and
displayed in the groups. You can scroll through the datasets to see

Changing FitMacroIVInf Options To change FitMacroIVInf options, first ensure that the number
of compartments (Nb Comp) you select is consistent when you
2. Click Set in the Global Options column of the Fit

MacroIVInf row. The Options Setup dialog appears.
Yobs 1/ Y observed

graphs

Changing Fitting PK/PD IV To change fitting PK/PD IV infusion options:

Infusion Options

FitPK/PD_IVInf row. The Options Setup dialog appears.

Linear
Log-Linear
Emax
Emax Inhibition
Hill
Hill Inhibition

variable)

Yobs 1/ Y observed

graphs



10. Creating Tables and Scripts
The following chapter provides information on creating Tables
and Scripts in Kinetica.

Creating Tables and Scripts
Creating Tables and You can successfully create and save tables and scripts using the
Table Assistant wizard. The Table Assistant creates tables by
Scripts using the directly accessing Kinetica files (files with a .kdb extension). A
Table Assistant table script file is also generated each time a table is created using
the Table Assistant. This script file can be saved in the Tables
pane and the current .kdb file. This enables you to build lists of
different tables, which can then be re-created by a single mouse
click. The tables are re-created using the last copy of computed
data in the active .kdb file. The same table script is saved to the
template so that users could use the same template with new
datasets.

Table Assistant The Table Assistant wizard is accessed by selecting

Tools/Assistants/Table from Kinetica’s main menu.
Wizard
The Table Assistant wizard is a series of dialogs that simplifies the
creation of a table and guides you through the process step-by-
step. You select a template, variable parameters, descriptive
statistics on datasets with the same grouping factors, summary
statistics, table formatting and conversion criteria, and save a table
script file.
To use the Table Assistant wizard, read the instructions in each

dialog to help you enter information and follow the steps in the
procedure. You can move back and forth between the dialogs and
change information as required until you complete the wizard.
You can exit without saving the information at any point before
completing the wizard by clicking Cancel.
The Table Assistant wizard has 5 steps. These steps are explained
in more detail in the information that follows.
Table Assistant - Step 1 of This dialog is used to select a template for the new table. Nine
5 Dialog templates, named "Structures" are provided. The content of the
templates is listed in the following table.
Structure Group Cross ID Variables Variables Descriptive Summary

Variables Variables Statistics
Statistics
1 √ √ √ optional
3 √ √ √ √ optional
6 √ √ √ √ √ optional
7 √ √ √ √ √ optional

Structure Group Cross ID Variables Variables Descriptive Summary

Variables Variables Statistics
Statistics
10 √ √ √ NA
11 √ √ √ NA
Note The template you choose will dictate the variables

available for selection in the Table Assistant - Step 2 of 5 dialog.
It will also determine the availability of the dialogs within the
procedure. ▲
Table Templates The following illustrations provide an example of each of the

templates available for selection in the Table Assistant - Step 1 of
5 dialog.
Figure 10-1. Table Structure One

Figure 10-2. Table Structure Two
Figure 10-3. Table Structure Three

Figure 10-4. Table Structure Four
Figure 10-5. Table Structure Five

Figure 10-6. Table Structure Six
Figure 10-7. Table Structure Seven

Figure 10-8. Table Structure Eight
Figure 10-9. Table Structure Nine

Figure 10-10. Table Structure Ten
Figure 10-11. Table Structure Eleven

Table Assistant - Step 2 of This dialog is used to select the table variable parameters. These
5 Dialog parameters are described in the table below.
Group Variable Identify data in adjacent columns
Appear as a column in the new table
Printed only when the value of a Group Variable changes
You can specify one or more Group Variables, if required
Rows in the new table will be sorted by Group Variables, then ID

Variables (if present)
Cross Variable Divides data into separate columns, one for each Cross Variable
defined
ID Variable Identify data in adjacent columns (e.g. Period, Age)
You can specify one or more ID Variables, if ID Variables are included

in the template you selected
If you choose to include summary statistics for the new table, statistics
are NOT included for ID variables
Rows in the table are sorted by ID Variables
Variable Data that is filled into the new table
If you choose to include summary statistics for the new table, statistics
ARE included for ID variables
Note The availability of the table variables is dependent on the

template selected in the Table Assistant - Step 1 of 5 dialog. If a
template does not include a particular variable (e.g. ID Variable),
the variable box appears gray to indicate that it is disabled. ▲

Table Assistant - Step 3 of This dialog is used to select the descriptive statistics to calculate
5 Dialog within datasets with the same grouping factor. For example, you
may want to calculate and display the Mean, Min and Max of all
datasets within each Treatment.
Note You must select at least one statistical test. ▲
Table Assistant - Step 4 of This dialog is used to select the summary descriptive statistics you
5 Dialog want to calculate across all datasets. For example, you may want
to calculate and display the Mean, Median, Geometric Mean and
Standard Deviation of all datasets, regardless of a grouping factor
such as Treatment.
Table Assistant - Step 5 of This dialog is used to specify the following characteristics for the
5 Dialog table:
• Table title
• Page layout preference (Portrait or Landscape)
• Font and font size for column titles and table body text
• Margins (top, bottom, left, and right)
• Datasets to include
For more information, see the section, “Selecting the Datasets

Dialog” in this chapter.
This dialog is also used to specify conversion criteria for all data
(summary statistics) contained in the table (optional). You can
specify:
• Number of decimal places, or
• Number of significant digits with or without scientific

notation.

For example, if the value for a sample is 103.9056912367, you

select the Number of significant digits with Scientific notation
option, and you specify four decimal places for the data display,
the notation will appear as follows:
1.039E3
You can specify conversion criteria for each column that appears
in the table. If you do not specify conversion criteria for a
column, all calculated decimal places for the value are used to
display summary statistics for the variable in the final table, by
default.
Note Statistics are calculated from raw numbers as they are

entered by you, not from formatted values that may appear
rounded. ▲

Selecting the Datasets This dialog is accessed by selecting the Dataset Selection check
Dialog box in the Table Assistant – Step 5 of 5 dialog. The Selecting the
Datasets dialog is used to select one or more datasets to include in
the new table. You can:
• Manually select one or more datasets
• Select all datasets
• Select subsets of datasets to include in the table, by specifying

a single dataset textual or numeric field that filters across all
datasets.
Note If you do not make any selections in this dialog, all

datasets will be included in the table, by default. ▲
To create tables and scripts using the table assistant wizard and
Excel
1. Select Assistants and then Table from the Tools menu. The
Table Assistant - Step 1 of 5 dialog appears.
Figure 10-12. Table Assistant – Step 1 of 5

2. Select a template from the available list and click Next. The
Table Assistant - Step 2 of 5 dialog appears.
3. Select a parameter from one of the available lists by dragging

and dropping the variable into the appropriate area.

Specifying Group Variables To specify group variables:

(optional)
1. Drag the Study Field(s) that you would like to include as
group variable(s) to the Group Variables area of the dialog.
2. To change the order of the group variables, click the Up or

Down arrow in the Group Variables area of the dialog.
Specifying Cross variables To specify cross-variables:, drag the Study Field(s) that you would
like to include as cross variables to the X Cross Variables area of
the dialog.
Specifying ID Variables To specify ID variables, drag the Study Field(s) that you would
like to include as ID variables to the ID Variables area of the
dialog.
Note You must specify at least one ID Variable if ID Variables

are included in the template that you selected in the Table
Assistant - Step 1 of 5 dialog. If you selected Structure 8 as the
template and you wish to use the transpose function that it
provides, you must select a Study Field (e.g., SbjName) that
uniquely identifies the study subject. ▲
Specifying Variables To specify variables:
1. Drag the Study Field(s) that you would like to include as

variables to the Variables area of the dialog.
2. To change the order of the variables, click the Up or Down

arrow in the Variables area of the dialog.

Specifying Data Set Fields To specify data set fields:

(available for templates 8 and 9
only)
1. Select a Worksheet name from the available list.
2. Drag the appropriate Column Name for time into the Time
area of the dialog (one column name only).
3. Drag the appropriate Column Name for concentration into

the Concentration area of the dialog (one column name
only).
4. Click Next. The Table Assistant - Step 3 of 5 dialog appears.

Selecting Statistics Based on To select statistics based on grouping factors:

Grouping Factors
• To select all of the descriptive statistics in the Available

list, click on the >> button. The list of available statistics
moves to the right-hand side of the screen under the
Selected list.
• To move the entire list of selected statistics back to the

Available list, click <<.
• To move a statistic from the Available list to the Selected

list, highlight the statistic(s) and click >. The descriptive
statistics move to Selected.
• To move a statistic from the Selected list to the Available

list, highlight the statistic and click <.
2. Highlight the appropriate statistic and click the Up arrow or

Down arrow to move a descriptive statistic in the Selected list
up or down.

Selecting Summary Statistics To select summary statistics:
• To select all of the summary statistics in the Available list,

click on the >> button. The list of available statistics
moves to the right-hand side of the screen under the
Selected list.
• To move the entire list of selected statistics back to the

• To move a statistic from the Available list to the Selected

list, highlight the statistic(s) and click >. The summary
statistics move to Selected.
• To move a statistic from the Selected list to the Available

list, highlight the statistic and click <.
2. Highlight the appropriate statistic and click the Up arrow or

Down arrow to move a summary statistic in the Selected list
up or down.


Specifying Title and Formatting To specify title and formatting characteristics:

Characteristics
1. Enter a name for the new table in the Table title field. The
table title is a text label placed at the top of the table. If you
do not enter a name, the Table Assistant uses the default title
“EP Table.”
2. Specify page layout, font and font size, and margin

preferences for the new table.
3. Click the Symbolic Status Flag check box if you would like to
report flagged data with both a symbol and a number (e.g.
<0.04), otherwise flagged data will be reported descriptively
(e.g. undetectable, outlier).
Specifying Conversion Criteria To specify conversion criteria:

(optional)
1. Click the Conversion check box.
2. Specify one of the following formats in the corresponding

spin box:
• Number of decimal places to display
• Number of significant digits with scientific notation.

When this option is chosen, the check box sets the data to
be displayed in the scientific format, as opposed to default
numeric format.
3. To specify conversion criteria for an individual variable, select

the variable from the Choose the variables to format list and
click >.
4. Specify the display for the variable using the spin box in the
Specify Data Format area of the dialog.

Specifying BLQ Handling To specify BLQ handling criteria:

(optional)
1. Select the option under the drop-down menu for BLQ data
2. If user-defined LLOQ is selected:
a. Map the column for LLOQ values
b. Select the LLOQ setting
BLQ handling The BLQ Data option lists different ways of handling below the
limit of quantification data by selecting:
less than symbol;
• Set as 0: Data with “<” will assume the value of 0;
• Set as missing: Data with “<” will be treated as missing;

data as 0;
• User-defined LLOQ, if checked, will override the BLQ data

LLOQ/4.
Export to SigmaPlot (optional) The export to SigmaPlot option is only available for Tables 2, 8
(transposed), and 9. To specify data export to SigmaPlot for
plotting, check the Export to SigmaPlot box.
• The group variable specify the sorting of data to different

tables based on the grouping variable.
• ID Variable becomes the column header of the SigmaPlot

tables.

• If ID variable is not available, the statistical parameters

become the column header of the SigmaPlot tables.
Specifying Data Set Information To specify data set information to include in the table:
to Include in the Table (optional)
1. Click the Dataset Selection check box. The Selecting the
Datasets dialog appears.
Figure 10-17. Table Assistant – Selecting the Datasets

Dialog
2. Specify one of the following in the Dataset Selecting area of

the dialog:
• Manual Select
• Criteria Setting
• Select All. If you make this selection, all data in the .kdb
file will be included in the table.

• To select all of the datasets in the Available list, click on

the >> button. The list of datasets moves to the right-
hand side of the screen under the Selected list.
• To move the entire list of selected datasets back to the

• To move a dataset from the Available list to the Selected

list, highlight the dataset(s) and click >. The datasets
move to Selected.
• To move a dataset from the Selected list to the Available

list, highlight the dataset and click <.
4. Select the appropriate textual or numeric field from the Field

list. Kinetica lets you to select combination of filter fields. For
example, select the text field DrugName.
5. Select the appropriate operator from the Operators list. For

example, select =.
• For text fields, select the appropriate criteria from the

Criteria list. For example, select B.
• For numeric dataset fields, enter the appropriate

numerical value.
• Click Cancel to exit the Selecting the Datasets dialog and

return to the Table Assistant – Step 5 of 5 dialog.
• Click Finish to complete the Table Assistant wizard, load

Excel and generate the table.

Saving Table Script Files To save table script files:
1. Return to Kinetica. A message appears prompting you to save

the table script (i.e. store the table creation script inside the
Kinetica study (a .kdb file)):
Figure 10-18. Prompt for Saving Table Script
2. Click Yes to save the script. The Export Script Name dialog
appears.
Figure 10-19. Export Script Name Dialog
• Click Cancel. The table remains inside Excel.
• Enter a name for the table script in the Export Script

Name field. The name is added to the list of other table
scripts that may already be embedded inside the kdb file.
Click OK. The Excel table script and table appear inside
the Tables pane.

Regenerating If you have embedded table scripts inside Kinetica, you can
recreate the tables without using the Table Assistant.
Embedded Tables
from Script Files To recreate a table:
1. Open the appropriate .kdb file. Kinetica loads all table scripts
saved in the study file inside the Tables pane.
2. Double click on the appropriate Table Script name in the

Tables pane to regenerate the table using the current data in
the study.

Deleting a Table You have the option to delete a table script at any time. When
you delete a table script, it is removed from the .kdb file and the
Script Tables pane.
To delete a table:
1. Select Embedded Objects then Tables from the Tools menu.

The Embedded Script dialog appears.
Figure 10-21. Embedded Table Script Dialog
2. Highlight the table script you want to remove and click

Remove.
3. Click OK to exit the dialog. The table script is removed from

the Tables pane and the .kdb file.

11. Population
Pharmacokinetics (PK)
Population pharmacokinetics is the study of the variability in
drug disposition between individuals when standard dosage
regimens are administered. The following chapter provides
information on PK within Kinetica.

Population Pharmacokinetics (PK)
Introduction to Population pharmacokinetics is the study of the variability in

drug disposition between individuals when standard dosage
Population PK regimens are administered. Because of logistical and ethical
Analysis in Kinetica reasons, only relatively sparse samples are taken and available for
analysis in many clinical trials. Therefore, traditional
pharmacokinetic analysis, which involves the determination of an
individual's pharmacokinetic parameters, is not feasible. The
methodology in population pharmacokinetics focuses on the
central tendency of the pharmacokinetic information and is
capable of analyzing such sparse data. This can lead to a better
prediction of the dose-response relationships in future studies.
Kinetica is also a software package for population

pharmacokinetic analysis using nonlinear mixed-effect models. It
can estimate the parameter distribution for the population, as
well as assess the contribution of inter-individual variabilities
physiologically and pathologically (covariates) to individual
parameter values. Covariates can be age, body weight, hepatic or
renal function, or co-administration of other drugs, for example.
Kinetica applies the EM algorithm to conduct nonlinear mixed-

effect model analysis.
STEP E: Conditional Expectation (Bayes)
The individual parameters in the model are estimated assuming

that they have a known prior distribution (mean + variance) and
a known residual error distribution (mean + variance).
STEP M: Likelihood Maximization
Given the individual parameters computed in Step E, the ML

posterior population mean and variance are computed.

Model Evaluation Model evaluation can be conducted through residual analysis, the
Akaike Criteria (AIC), Schwartz criterion (BIC), objective
function (OBJ), or the log likelihood function. The Evaluation
Graphs in Kinetica enable you to evaluate the distribution of
computed parameters, the distribution of the residual error, the
weighting schemes, as well as the prediction of the individual and
population profiles, with the option to display the confidence
interval. Kinetica estimates the expected individual parameters
given the populations' estimated values (using a MAP procedure),
and then computes appropriate statistical tests to evaluate the
distribution properties of the differences between the expected
and the observed data. For more information, see “Appendix A
Population Methodology.”
Start
Fixed effect parameters : β(k)

Observations :
&
time,
Variance matrix of random effect
concentrations,
parameters: C(k)
covariates.
&
Step E Error variance : σ(k)
Individual parameters: No
βj(k+1)
Stop
? Yes
Fixed effect Variance of

Step M parameters: +
random effect + Error variance :
σ(k+1)
β(k+1) parameters
C(k+1)
Figure 11-1. EM Algorithm Flow Chart

Features of The features included in Kinetica Population are listed in the

following table.
Population PK
Analysis in Kinetica Feature Description
User interface As in Standard Kinetica (see the section,

“Using the Kinetica Workspace” in the
chapter “Starting Kinetica”)
Import/Export As in Standard Kinetica (see the section,

data “Importing and Exporting Data”)
Graphic engine As in Standard Kinetica (see the chapter,

“Working with Graphs”)
Standard analysis All mathematical/statistical analyses in

standard Kinetica are available in Kinetica
Population
Structural model Kinetica contains a pre-defined library of

PK/PD. Write your own models using
either the Population Designer or Kinetica
Macro language (see the section, “Working
with the Population Designer” in this
chapter, and Appendix B)

Feature Description
Covariate models Two options to build covariate models are

offered by Kinetica Population:
The first option is user-defined and enables

you to select the PK/PD parameters, then
associate them to one or more covariables
(for more information, see the sections,
“Population Methodology” and “Running
the Analysis with Covariable(s)” in this
chapter)
The second option makes use of a Stepwise

forward method to screen the potential
covariates. The final covariate models are
obtained through multiple linear regression
between the parameters and the covariables
(for more information, see Appendix A
and the section, “Running the Analysis
with Covariable(s)” in this chapter)
Interindividual Parameters can be calculated assuming a

variability normal or a Log Normal distribution (see
Appendix A and the section, “Estimating
Initial Parameter Values” in this chapter)

Feature Description
Residual error There are three types of residual errors:

additive, proportional, and the
combination of both additive and
proportional
There are four different scenarios for

variance:
The variance is a known constant
The variance is an unknown constant
The variance is proportional to the square

of the dependent variable
The variance is proportional to the

dependent variable
(see Population Methodology – Appendix

A)
Initial Parameter These values are provided either by the

Estimates user or by the Initialization Assistant (for a
single dose). The Initialization Assistant
applies the stripping method to naïve
average data (NAD), naïve pooled data
(NPD), or individual data (standard two-
stage method) to obtain the parameter
values. These values are then used as initial
estimates for the EM algorithm. For more
information, see the section, “Estimating
Initial Parameter Values” in this chapter.

Feature Description
Graphic Generates:
Evaluation
Individual observations and predictions
Individual observations together with the

population mean curve
Individual observations against individual

predictions
Weighted residuals against predicted values
Residuals against predicted values
Residual error distribution
Parameter distribution
For more information, see the section,

“Working with Kinetica Population
Graphs” in this chapter.
In addition, you can use Kinetica Population to:
• Import/export data and graphs
• Create datasets
• Select or modify the computational methodology by writing

user-defined soft-coded methods
• View individual and study results.
Note To use Kinetica Population, you must insert at least one

population PK/PD method after entering the input data and
inserting the necessary variables. ▲

Kinetica Population The wide variety of hard-coded methods in the Population

Method directory is listed and categorized based on:
PK/PD Methods
• Route of administration (e.g. IV Bolus, Extravascular (first
order absorption), IV Infusion, Zero Order Absorption
(single dose only) models for single and multiple dose.
• Compartment number (e.g. 1 Comp, 2 Comp, 3 Comp).
• Type of pharmacodynamic model. For more information

related to pharmacodynamic modeling, see Population
Methodology – Appendix A.
Each hard-coded method is uniquely designed to generate specific

output columns and variables for numerous types of population
templates. All population PK/PD methods contain the prefix
“PopFit.”
Note The naming conventions for hard-coded methods and

templates are identical. ▲
For a complete list of the generated outputs for each method, see
the sections, “Single Dose Population PK Methods and
Compartments”, “Multiple Dose Population PK Methods and
Compartments”, and “PD Population Methods and Output
Parameters” in this chapter.
Note You can also create soft-coded methods in the Macro

Editor to meet your own requirements. For more information,
see the section, “Working with Population Designer” in this
chapter and in Appendix B. ▲
The population PK/PD methods (hard-coded in C++) are listed

in the following table.
Population Method Function in Kinetica
PopFitMicroIVBolus1comp Single dose intravenous bolus micro constants using 1-

compartment model


compartment model.

compartment model.
PopFitMicroExtravascular1comp Single dose extravascular micro constants using 1-

compartment model.

compartment model.

compartment model.
PopFitMicroIVInf1comp Single dose intravenous infusion micro constants using

1-compartment model.


PopFitMicro0orderinput 1comp Single dose zero order micro constants using 1-

compartment model.
PopFitMicro0orderinput 2comp Single dose zero order micro constants using 2-

compartment model.
PopFitMicro0orderinput3comp Single dose zero order micro constants using 3-

compartment model.
PopFitBolusInput1comp Single dose intravenous bolus using 1-compartment

model. Clearance is used as a parameter.
PopFitBolusInput2comp Single dose intravenous bolus using 2-compartment

model. Clearance is used as a parameter.
PopFitFirstOrderinput 1comp Single dose input using 1-compartment model.

Clearance is used as a parameter.

PopFitFirstOrderinput 2comp Single dose input using 2-compartment model.

Clearance is used as a parameter.
PopFitZeroOrderinput1comp Single dose zero order using 1-compartment model.
PopFitZeroOrderinput2comp Single dose zero order using 2-compartment model.
PopFitLinear Pharmacodynamic linear model.
PopFitLinearInhibition Pharmacodynamic log linear model.
PopFitSigmoidal Pharmacodynamic Sigmoid model.
PopFitSigmoidal Inhibition Pharmacodynamic Sigmoid Inhibition model.
PopFit Emax Pharmacodynamic Emax model.
PopFit Emax Inhibition Pharmacodynamic Emax Inhibition model.
PopFitIVBolus1CompMultiDose Multiple dose intravenous bolus micro constants using



PopFitExtravascular1CompMultiDose Multiple dose extravascular micro constants using 1-

compartment model.

compartment model

compartment model.
PopFitIVInfusion1CompMultiDose Multiple dose intravenous infusion micro constants

using 1-compartment model.




Inserting a You can select the hard-coded population PK/PD methods for
fitting in the Methods dialog. We call these methods models
Population PK/PD because they are specific methods for modeling data rather than
Method simple functions. When you choose a population PK/PD method
from the Methods dialog, the input and output parameters can be
viewed along with a brief explanation of what the method
computes.
Note If a population PK/PD method is being shared by more

than one worksheet, be sure to rename the output parameters
found in the Method dialog. If you do not perform this
procedure, the calculations from the second worksheet will
override the first. ▲
To select a population PK/PD method:
1. Launch Kinetica and enter the input data.
• Create your own soft-coded model method by clicking

Macro Editor in the Study pane.
• Use Designer to create your method graphically by

selecting Designer then Population from the Tools menu
3. Select Pop Method from the Insert menu. The Method

Selection dialog appears. We will use this option for this
example.

4. Select a population method from the available list (e.g.

PopFitMicroExtravascular1comp method) to activate
Kinetica Population.
5. Make the appropriate selections under the User names and

Parameter columns corresponding to the Input Cols&Vars,
Output Cols and In/Out Vars columns by clicking on the
associated drop down lists. Parameters have a Yes or No
option. If you select Yes, you are prompting Kinetica to
calculate the parameter. If you select No, you are specifying
that there is an existing value for the parameter and thus the
parameter will not be calculated.
6. Click Datasets. The Select Dataset dialog appears.

Figure 11-4. Select Dataset Dialog
7. Use the Ctrl key and mouse to select a particular range of

datasets or click Select All to include all datasets.
8. Click OK to exit the Select Dataset dialog.
9. Click OK to exit the Method Selection dialog.

Modifying Global You can view or modify population PK/PD method options after
a population PK/PD method is inserted using the Options Setup
Options dialog. All inserted population PK/PD methods contain the same
options.
Options Setup Dialog This dialog is accessed by clicking Methods in the Methods pane
and then clicking Set under the Global Options column of the
appropriate population PK/PD method. The selections in the
Options Setup dialog are described in the following table.
Note These options can be modified before and after running

an analysis without covariables. For more information, see the
sections, “Estimating Initial Parameter Values” and “Running the
Analysis without Covariable(s)” in this chapter. ▲
Option Description
Initialization With Population parameters - Select this

option to use prior population parameter
distribution to run the EM algorithm
With Individual Parameters: If the

individual parameters are known, you can
select this option to rerun the EM
algorithm
Use Simplex for Yes – Select this option to use Simplex to

the First Step search for the minimum point for the first
step
No – Select this option if you do not want

to use Simplex
Datasets Select this option to choose the set of

datasets to analyze

Modifying Global Options To modify global options:
2. Click Set under the Global Options column of the

appropriate Population PK/PD method. The Options Setup
dialog appears.
Figure 11-5. Options Setup Dialog
3. View or modify the options as required then click OK to save

the information and exit the dialog.

Routes of There are four primary routes of administration pertaining to

single dose situations and three primary routes of administration
Administration pertaining to multiple dose situations, as described in the
following table.
Route of Description
Administration
IV Bolus This method is used when the kinetic

profile of a drug was generated as a result
of an intravenous bolus administration.
Extravascular This method fits data for all routes other

than IV Bolus and IV Infusion (e.g. oral
administration, I.M, etc.). The general
condition for use is an input (or
absorption) following a first order. For this
reason, Kinetica provides an Output
Variable Ka you can fit with or without
lag-time.
IV Infusion This method is used when you have a

kinetic profile of a drug generated as a
result of an administration with a known
IV infusion duration value (as an input).
Zero Order Input This method is used when you have a

kinetic profile with a zero order input
function that is not an IV Infusion. This
case is possible with an oral, I.M
administration, etc. The Input duration
(equivalent to the Infusion duration in the
IV Infusion) is an Output Variable and is
then estimated by Kinetica.
Note This route of administration is not

available for multiple dose situations. ▲

Compartment Number The routes of administration can be further subdivided by

(1Comp, 2Comp, 3Comp) compartments as we described below in more detail.
• 1Comp (one compartment model)
• 2Comp (two compartment model)
• 3Comp (three compartment model).
They can be further subdivided by PK single dose and PK

multiple dose, as follows:
Single Dose Methods In the case of single dose administration, execution of population
data is accomplished by providing input data consisting of Time,
Concentration, Dose and *Infusion Duration, as dictated by the
Single Dose Population PK/PD method you want to insert.
Note *Infusion Duration is an input when the route of

administration is an IV Infusion. Infusion Duration is a
calculated output if the route of administration is a Zero Order.
▲
Inputs are numeric or text variables and columns where you must
enter data so that Kinetica can successfully complete the analysis.
Outputs are numeric or text variables and columns where
Kinetica displays the results of the computation.
Note All PK single dose methods require the same variable and
column input. ▲
Data input (user-entered dataset numeric or text field values):
Data input (user-entered dataset column values)
T (or X) – Time
C (or Y) – Concentration

Note By default, Kinetica will identify Time and

Concentration values entered under X and Y columns,
respectively. If you want to modify these settings, you must first
delete the population method. You can do this using the Select
Columns and Variables to Remove dialog, accessed by selecting
Remove Last Pop Method (or Remove all Pop Methods) from
the Edit menu. Alternatively, if you have not yet inserted a
method, insert the population PK/PD method and select the
appropriate User Names and Parameters in the Method Selection
dialog. ▲
This table lists all Single Dose Population Methods and

associated output parameters, categorized by compartment
number.
Single Dose Population Output Parameters

Methods
Population Method 1 Compartment 2 Compartment 3 Compartment
PopFitMicroIVBolus Volume, Kel Volume, Kel, K12, K21 Volume, Kel, K12,
K21, K13, K31
PopFitMicro Volume, Kel, Ka, Volume, Kel, Ka, Lag, Volume, Kel, Ka,
Extravascular Lag K12, K21 Lag, K12, K21, K13, K31
PopFitMicroIVInf Volume, Kel Volume, Kel, K12, K21 Volume, Kel, K12,
K21, K13, K31
PopFitMicro0orderinput Volume, Kel, Volume, Kel, Infusion Volume, Kel,

Infusion Duration Duration, K12, K21 Infusion Duration,
K12, K21, K13, K31
PopFitBolusInput Volume, CL Volume, CL, K12, K21
PopFitFirstOrderinput Volume, CL, Lag, F, Volume, CL, Lag, F,

Ka Ka, K12, K21

Single Dose Population Output Parameters

Methods
PopFitZeroOrderinput Volume, CL, Volume, CL,

InfusionDuration InfusionDuration, K12,
K21
Note Individual parameters are stored in the All Variables

worksheet. Population parameters are stored in the Study
worksheet. Population parameter names are displayed as
“Study.parametername.” ▲
Multiple Dose Methods In the case of multiple dose administration, execution of

population data is accomplished by providing input data
consisting of Time, Concentration, Administered Time, and
Administered Dose columns, as dictated by the Multiple Dose
Population PK method you want to insert.
T – Time
AdminDose – Amount of drug administered
AdminTime – Time of drug administration
*InfusionDuration – Duration of drug infusion

(PopFitIVinfusionMultiDose method only)
Choose to identify the administration route:
• Extravascular
• IV infusion
• IV Bolus.


This table lists all Multiple Dose Population Methods and

associated output parameters, categorized by compartment
number.
Multiple Dose Population Methods Output Variables
Population Method 1 Compartment 2 Compartment 3 Compartment
PopFitIVBolusCompMulti Volume, Kel Volume, Kel, K12, Volume, Kel, K12,

Dose K21 K21, K13, K31
PopFitExtravascularComp Volume, Kel, Ka, Volume, Kel, Ka, Volume, Kel, Ka,
MultiDose Lag Lag, K12, K21, K13,
Lag, K12, K21 K31
PopFitIVInfusionComp Volume, Kel Volume, Kel, K12, Volume, Kel, K12,

MultiDose K21 K21, K13, K31
Pharmacodynamic Methods In the case of pharmacodynamic templates, execution of

population data is accomplished by providing input data
consisting of Concentration and Effect columns, as dictated by
the PD population method you want to insert.
Effect – Drug Effect
This table lists all Population PD Methods and associated output

parameters.
PD Population Method Output Parameters
All Variables Worksheet
PopFitLinear S, E0

PD Population Method Output Parameters
PopFitLinearInhibition S, E0
PopFitLogLinear S, E0
PopFitLogLinearInhibition S, E0
PopFitSigmoidal E0, Emax, n, EC50
PopFitSigmoidal Inhibition E0, Emax, n, EC50
PopFit Emax E0, Emax, EC50
PopFit Emax Inhibition E0, Emax, EC50


Kinetica Population This table lists output columns for all Population Methods.
Output Columns
Note The output columns for all Kinetica Population PK
methods are the same. ▲
Output Column Description
Ycalc Computed values of dependent variable for

each individual
Residuals Difference between Ycalc and Yobs for each

individual
Weight Weighting for each individual
Weighted Residual adjusted according to a selected

Residuals weighting scheme, e.g. 1,Ycalc, Ycalc2,
Yobs, Yobs2 for each individual
Iwres Residual adjusted according to standard

deviation calculated from variance matrix
Isd Square root of the diagonal in the variance

matrix
Pred Predicted values of dependent variable

computed with the population mean values
of parameters
Sd Standard deviation of population prediction
Wres Residual adjusted according to standard

deviation calculated from variance matrix
for population

Kinetica Population In order to understand how to use Kinetica Population templates,

we suggest that you study the following example. This way you
Templates can try running an analysis to understand how Kinetica
Population computes results before using your own data. After
you try the example, you can open the empty template and enter
your data by, either: a) cutting and pasting the data, or b)
importing the data using the Import Assistant. You can then
rerun the analysis. For more information related to the Import
Assistant, see the chapter, “Importing and Exporting Data.”
The following example is applicable to all Population templates,

with small variations. These variations are indicated, as needed.
Note The difference between .kdb and .ktp files: .kdb file: A
file that contains calculated results dependent on the method(s)
embedded within it. .ktp file: A template that contains methods
with no calculated results. A template (or .ktp file) can be used
repeatedly for future analysis. ▲
Running an Example A drug dose of 100 mg was administered via IV Bolus. The
Template concentration-time course was sampled from the plasma,
expressed in mg/L and h respectively. A one-compartment model
(PopFitMicroIVBolus1com
was used to analyze this example.
p single dose)
To open the PopFitMicroIVBolus1comp template:
appears.
2. Select the Population tab.
3. Click on the PopFitMicroIVBolus1comp icon and select the

Open with Data check box.

Figure 11-6. New Analysis Dialog showing Population Tab, PopFitMicroIVBolus1comp.ktp, Open
with Data selected.
4. Click OK. The data appears in the workspace.
5. Examine the data, as required.
Note When you are working with your own data, we

strongly advise that you examine the data carefully. Review
graphs, check for outliers, missing values and inconsistencies.
▲
6. To estimate initial parameter values, see the section,

“Estimating Initial Parameter Values” in this chapter.

Estimating Initial After you open the template, you estimate initial parameter values
Parameter Values for the EM algorithm to get the best possible fitting for the data
using the Set Initial Parameter Values dialog.
There are two ways of entering initial parameter estimates:
• Manually
• Using the Initialization Assistant.
You can manually enter values for all templates. However, the
Initialization Assistant is not available for multiple dose or PD
templates.
Using the Set Initial Parameter This dialog is accessed by selecting Set Initial Parameters from the
Values Dialog Population menu. The dialog is divided into several sections:
1. Select Inserted Population Method – contains all inserted

Population methods within a template. You can select the
appropriate method by clicking on the drop down list. The
initial parameter values you set in this window and the error
model correspond to the population method you selected.
2. Enter Initial Parameter Estimation – applicable to manual

data entry (without using the Initialization Assistant). You
enter values for each parameter under the Values column.
You also have the option to enter values for the remaining
columns, as required.
Column Description
Minimum Lower bound in parameter estimation. For

normal distribution, the default value is set
at value/20. Only used in the random
search algorithm.
Maximum Upper bound in parameter estimation. For

normal distribution, the default value is set
at value*100, by default. Only used in the
random search algorithm.

Column Description
Init.Variance Initial estimation of variance for

population parameters.
Init.CV 100*population mean/population SD.
Distribution Used to select the population parameter

distribution property, either normal or log
normal. Convert values interchangeably
(Log to Normal). If you choose a log
normal distribution, the initial estimates,
minimum and maximum are automatically
converted from normal distribution.
3. Select Error Model – defines the error variance according to

the Sigma and the Weighting function. The Error Variance
models are described in the following table.
Column Description
Sig1(fixed constant) Kinetica assumes that the variance of

the error model is a known constant.
Sig1 Kinetica assumes that the error variance

(homoscedastic) is the same for all the measurements,
but it is unknown.
Sig1*Weight+Sig2 You can set Sig2 to 0 for heteroscedastic

error structure. There are 4 different
weighting schemes:
~ Y – Kinetica assumes that the error

variance is proportional to ycalc or yobs
~ Y^2 – Kinetica assumes that the error

variance is proportional to the ycalc^2
or Yobs^2.
Sig1*Weight+Sig2 If Sig2 is not set to 0, this is a

combination error structure,
homoscedastic+ heteroscedastic.

Column Description
Link Model This option is used for PK/PD

simultaneous fitting.
4. Initialization Assistant Wizard…The Initialization wizard is a

series of dialogs designed to aid in the process of estimation
using one of the available methods.
To use the Initialization Assistant wizard, read the instructions in

each dialog to help you enter information, and follow the steps in
the procedure. You can move back and forth between the dialogs
and change information as required until you complete the
wizard. You can exit without saving the information at any point
before completing the wizard.
The Initialization Assistant wizard has 3 steps. Step 2 can be

completed by following the directions on the dialog and in the
procedure. Steps 1 and 3 are explained in more detail in the
following descriptions.
Initialization Assistant Wizard - This dialog is used to select an initialization method. These
Step 1 of 3 Dialog methods are described in the following table.

Initialization Description
Method
Naive Average Creates new datasets by calculating the

Data (NAD) mean time and concentration values for
those datasets (or individuals) with the
same dosing regimen
Creates initial parameter estimates for the

EM algorithm by applying standard
compartment PK analysis on the new
datasets. If there is more than one new
dataset, the mean values of the parameters
will be used as initial estimates for the EM
algorithm
By selecting this method, when you open

the exported .kdb file, you see that the
mean values were calculated using the
concentration values from all datasets.
Therefore, your dataset worksheet appears
to contain 1 or several datasets, depending
on the dosing regimen (see Initialization
Assistant Wizard - Step 3 of 3 Dialog
description)

Initialization Description
Method
Naive Pool Data Creates new datasets by gathering/pooling

(NPD) time and concentration values for those
datasets (or individuals) with the same
dosing regimen
Creates initial parameter estimates for the

EM algorithm by applying standard
compartment PK analysis on the new
datasets. If there is more than one new
dataset, the mean values of the parameters
will be used as initial estimates for EM
algorithm.
If you select this method, when you open

the exported .kdb file, all time and
concentration values (x and y columns,
respectively) for those datasets with the
same dosing regimen are displayed (stacked
one on top of the other) as one dataset (see
Initialization Assistant Wizard - Step 3 of 3
Dialog description)
Two Stage Creates initial parameter estimates for the

method EM algorithm by calculating parameter
values one dataset at a time using standard
compartment PK analysis
If you select this method, when you open

the exported .kdb file, time and
concentration values (x and y columns,
respectively) for all datasets are displayed in
one worksheet (see Initialization Assistant
Wizard - Step 3 of 3 Dialog description)
This dialog is also used to select a group. Both NAD and NPD
are accomplished using the “dosing regimen” grouping factor.
Only those datasets (or individuals) that have the same dosing
regimen can be grouped together. Each group corresponds to one
dosing regimen.

You also have the option to select Automatic Initialization for

Fitting. If you select this option, Kinetica will provide initial
values to conduct parameter estimation on the new datasets
generated from NAD or NPD, or on each individual dataset in
the Two Stage method. These initial values provided by Kinetica
are derived from the Stripping method.
Initialization Assistant Wizard - This dialog is used to:

Step 3 of 3 Dialog
• Select Group (required for NAD and NPD methods only)
• View the generated graph
• Export the data to a new .kdb file (optional)
• Review the calculated values for every available group.
There are two ways of adjusting parameter values (for example, if

you do not have a good fitting):
• You can manually edit the calculated values and click Reload
Graph to see the adjusted plot.
• You can select a parameter from the drop down list (e.g.
study.vol, study.kel), and adjust the plot by clicking the up or
down arrow (available for NAD and NPD methods only).
The percentage of change in the parameter value that occurs
each time you click an arrow can be adjusted by manually
entering a different numerical value in the field. The value is
set to 0.1, by default.
You can adjust parameters for two or more groups simultaneously

by clicking the icon in the Select Parameters row. If there is an
“X” in the box, Kinetica will recalculate the values. If there is no
“X,” the values will not be recalculated.
To estimate initial parameter values:
1. Complete the procedure for running an example template

(see the section, “Running an Example Template”
(PopFitMicroIVBolus1comp single dose) in this chapter).

2. Select Set Initial Parameters from the Population menu. The

Set Initial Parameter Values dialog appears.
Figure 11-7. Set Initial Parameter Values Dialog
3. Set options for Error Variance, Sig1, Sig2 and Weight, if

required. After running the Initialization Assistant, you can
readjust these values, if necessary.
• Manual entry: Enter values for each parameter in the

Value column and any other initial parameters, as needed.
Click OK to exit the dialog. To run the analysis, see the
section, “Running the Analysis without Covariable(s)” in
this chapter.
• Click Initialization Assistant. The Initialization Assistant

Step 1 of 3 dialog appears.

Figure 11-8. Initialization Assistant – Step 1 of 3
5. Select one of the following from the Select Initialization

Method list:
• Naive Average Data (NAD)
• Naive Pool Data (NPD)
• Two Stage Method.
For this example, we select NAD.
6. If you want to perform automatic fitting, select the

Automatic Initialization for Fitting check box. For this
example, we perform automatic fitting.
7. Click Group. The Select Group dialog appears.

Figure 11-9. Select Group Dialog
8. Select the appropriate check box and parameter from the drop
down list box. For example, select the Dose Group check box
and select Dose from the drop down list.
Note For intravenous infusion single dose population

methods, you must also select the Infusion Group check box
and then select the infusion duration variable from the
available list. ▲
9. Click OK to return to the Initialization Assistant Step 1 of 3

dialog.
10. Click Next. The Initialization Assistant Step 2 of 3 dialog

appears:

Figure 11-10. Initialization Assistant Step 2 of 3. If “Automatic Initialization for Fitting” was
unchecked in Step 1, initial parameter fields are blank and will need to be set manually.
• Manually enter initial estimates under Group.
• If you selected the Automatic Initialization for Fitting in

the Step 1 of 3 dialog, the estimated values are already
displayed (see figure below).

Figure 11-11. Initialization Assistant Step 2 of 3. “Automatic Initialization for Fitting” box was
checked in Step 1 so initial parameter value fields are populated here.
12. Click Next. The Initialization Assistant Step 3 of 3 dialog

appears. The results of the fitting are displayed. View the plot.
Edit the data, as required.

Figure 11-12. Initialization Assistant - Step 3 of 3
13. To complete the estimation, perform one of the following:
• Click the Back button to return to Step 1 of the

Initialization Assistant and repeat the procedure if results
are not satisfactory.
• Click Export Data to New KDB.
• Click Finish to conclude the wizard.
14. For this example, click Export to New KDB. The Export
Data to New KDB dialog appears.

Figure 11-13. Export Data to New KDB Dialog
15. Click the “…” button under the Select Path column. The
Save As dialog appears.
16. Enter a name for the .kdb file to be exported under a folder of
your choice and click Save.
17. Click OK to exit the Export Data to New KDB dialog.
18. Click Finish in the Initialization Assistant Step 3 of 3 dialog.

The estimated values appear in the Set Initial Parameter
Values dialog.

Figure 11-15. Set Initial Parameter Values Dialog after running Initialization Assistant.
19. Readjust the calculated values and options as needed.
21. To run the analysis, see the section, “Running the Analysis
without Covariable(s)” in this chapter. While you run the
analysis, you can also create different types of graphs
(Yobs/Ycalc, Wres/Ycalc, Res/Ycalc, Weighted Residual
Distribution, Parameter Distribution), transforming the
information generated by the calculated data into graphical
representations (see the section, “Working with Kinetica
Population Graphs” in this chapter).

Running the Analysis After you create initial parameter estimates for the EM algorithm,
without Covariable(s) you are ready to run the analysis without covariables. This
procedure must be performed before running an analysis
including a covariable.
The population pharmacokinetic parameters together with the

individual posterior estimates are computed under the
assumption that no dependency exists between the PK parameter
and the covariables. The relationship between the posterior
individual estimates and the covariables is investigated using
graphical exploratory function, statistical analysis, or a forward
selection of Stepwise algorithm, after the procedure for running
the analysis without covariables is completed.
The analysis is performed using the Running EM dialog. The

default setting for the maximum number of iterations is twenty-
five. When you reach the maximum, you have the option to add
an additional 25 iterations. An iteration is one run of the EM
algorithm. You can also change this default setting using the
Advance Fitting Options dialog. For more information, see the
section, “Performing Advanced Fitting” in this chapter.
To see the final results quickly, select a faster booster speed. To

see the results of each iteration, adjust the booster speed to low. If
you find the process too fast, adjust the booster speed. You can
pause at any time by clicking Pause.
To run the analysis without covariables:
1. Complete the steps for estimating initial parameter values (see

the section, “Estimating Initial Parameter Values” in this
chapter).
2. Select Run with No Covariables from the Population menu.

The Running EM… dialog appears.

Figure 11-16. Running EM Dialog
3. Adjust the Booster speed as required and click Start.
Note Max speed = one hundred percent of CPU used for

calculations. ▲
4. To pause the process at any time and review the data, click
Pause. To resume the process click Pause.
5. When the iterations are complete, you will see a green flag or
red flag. If you see a red flag, this indicates that an error
occurred. Adjust initial parameter estimate values, and rerun
the analysis. For more information, see the section,
“Estimating Initial Parameter Values” in this chapter.
6. Click Close. The Individual Graphs dialog appears.

Figure 11-17. Individual Graphs Dialog
View each dataset plot by clicking the arrows located at the top of
the dialog. You have the following options:
• Report Setup, Select Datasets, Export to Word, Export to

Gallery, and Nb of Columns – dictates the number of
columns that will be displayed on a page in Word (for more
information related to these export features, see the sections,
“Exporting Data to Microsoft Word and Microsoft Excel”
and “Exporting Data to Microsoft Word” in this chapter).
• Individual CI – plots the dataset curve including the upper

and lower confidence interval. By default CI is set to 95%.
You can modify this setting by clicking Probability for CI.
• Prediction – plots the individual dataset curve, predicted and

observed, with the population mean curve, predicted.
• Individual – plots the individual dataset curve, predicted and

observed.

Graphical Evaluation Graphical Evaluation displays the available Kinetica Population

graphs (for more information, see the section, “Working with
Kinetica Population Graphs” in this chapter).
1. For this example, click Graphical Evaluation and click OK.

The following message appears: “Are you sure you want to
close the individual graphs dialog box?” Click No to return to
the Individual Graphs dialog. Click Yes to view all the graphs
in the Gallery item of the Gallery pane.
2. To run the analysis with covariables, see the section,

“Running the Analysis without Covariable(s)” in this chapter.
Running the Analysis with After you run the analysis without covariables, you are ready to
Covariable(s) run the analysis with covariable(s). Only the covariables showing
a correlation with a pharmacokinetic parameter are used in the
analysis. The population parameters are now re-estimated taking
into account the relationship between the individual parameter
and the covariables. You can then compare the results obtained
from running the analysis without covariables to the results
obtained from running the analysis with covariables.
There are two ways to define a covariate model:
• Manually
• Using Stepwise Inclusion.
Note You can estimate the relationship between a parameter

and a covariable before running the analysis with covariables. To
do this, select the All Variables worksheet in the Study pane.
Highlight a particular parameter that you would like to
investigate and one covariable, and click the Show one graph
button on the toolbar. A graph is displayed in the Gallery. You
can also select Linear Regression from the Statistics menu to
generate a linear regression, and determine whether a linear
relationship exists between the selected parameter and the
covariable. For more information, see the chapter, “Performing
Statistical Analysis.” ▲

After you complete the procedure, you can repeat the analysis by
inserting more methods and variables, as required.
To run the analysis with covariable(s) by defining a covariate

model manually

chapter).
2. Complete the steps for running the analysis without

covariables (see the section, “Running the Analysis without
Covariable(s)” in this chapter).
3. Select Add with Covariables from the Population menu. The

User Defined Covariables dialog appears.
Figure 11-18. User Defined Covariables Dialog
4. Double click a parameter in the Parameters area of the dialog.

For this example, we will select study. Kel. The parameter

appears in the Current Expression of the Parameter Model

area of the dialog.
Note To change your selection, click Clear and then select

another parameter. ▲
5. Double click Add a Constant Value. The equation

study.Kel=Theta1 is inserted in the Current Expression of the
Parameter Model area of the dialog.
6. Double click a covariable(s) in the Covariables list. For this

example, select Age and click Add.
The covariate equation study.kel = Theta1 + Age*Theta2

appears in the Parameter Model List area of the dialog. You
can now set initial parameter estimates under the Value
column for Theta1 and Theta2.

Figure 11-20. User Defined Covariables
Note To add a covariable in an exponential relationship,

click the Power Model box. ▲
7. Enter initial value estimates. For this example, enter 0.1 for
Theta1 and -0.01 for Theta2.
8. Repeat the appropriate steps for other PK parameters, as

required.

Modifying the Equation To modify the equation:

(optional)
1. To change your selection, click Clear all equations and then
repeat Steps 38 to 41.
3. Select Run with Covariables from the Population menu. The

Running EM dialog appears.
4. Complete the appropriate steps for running the analysis

without covariables (see the section, “Running the Analysis
without Covariables” in this chapter).
Running the Analysis with To run the analysis with covariables using stepwise inclusion:
Covariable(s) Using Stepwise
Inclusion
chapter).

3. Select Add with Covariables from the Population menu. The

User Defined Covariables dialog appears.
4. Double click a parameter in the Parameters area of the dialog.

For this example, we will select study. Kel. The parameter
appears in the Current Expression of the Parameter Model
area of the dialog.
Note To change your selection, click Clear and then select

another parameter. ▲

5. Click Stepwise Inclusion. The Stepwise dialog appears.
Figure 11-22. Stepwise Dialog

6. Double click the appropriate covariable(s). For this example,

double click Age. The covariable moves to the Selected
Covariables list. Adjust the Significant Level, if required.
7. Click Run Stepwise. The values are displayed in the Stepwise

Output Result list.
Figure 11-23. Example – Stepwise Output Result List
8. Click Insert. The following message appears: “Add covariable

equation?”
9. Click Yes to insert the covariable equation(s). The equation(s)

is inserted in the Parameter Model List area of the dialog.
10. Repeat the appropriate steps for other PK parameters, as

required.

Modifying the Equation To modify the equation:

(optional)
1. To change your selection, click Clear all equations and then
repeat the appropriate steps.
3. Select Run with Covariables from the Population menu. The

Running EM dialog appears.
4. Complete the appropriate steps for running the analysis

without covariables (see the section, “Running the Analysis
without Covariable(s)” in this chapter).
Viewing Calculated Data After you run the analysis with covariables, you have the option
to generate descriptive statistics. The Study Info view displays
information about the data, estimated parameters and selected
options at different stages of the analysis. The window indicates
which data model is currently in use, displays the initial
parameter values, and the calculated population parameters using
the initial estimates. This file can be exported to Word.
To view calculated data in the Study Info view:

chapter).

3. Complete the steps for running the analysis with covariables

(see the section, “Running the Analysis with Covariable(s)” in
this chapter).
4. Select the Study pane and click on Study Info.

Performing Advanced The default settings for fitting options can be modified using the
Advanced Fitting dialog. Default settings vary depending on the
Fitting method you select. The settings can only be modified for one
method at a time. The fitting options are described in the
following table.
Fitting Option Description
Criteria for EM EM must be less than the number

displayed
Maximum number of The limit number of iterations for the

iterations for EM EM algorithm
Start criteria for E The initial criteria for E-step

fitting minimization
Final criteria for E The criteria for e-step minimization. If

fitting this criterion is satisfied, the E-step is
finished.
Maximum number of Maximum number of iterations for

iterations for E the E-step
Minimum value of The value used for the Levenberg-

Lambda for E Marquardt algorithm
Initial value of The start value of lambda before the

Lambda for E application of the Levenberg-
Marquardt algorithm
Derivation step The required numerical derivation

step
Coefficient for How the value is involved in the

Lambda variation of E variation of lambda
To modify default settings:

chapter).


3. Complete the steps for running the analysis with covariables

(see the section, “Running the Analysis with Covariable(s)” in
this chapter).
4. Select Options from the Population menu. The Advanced

Fitting Options dialog appears.
Figure 11-24. Advanced Fitting Options Dialog
5. Modify the settings for the fitting options, as required. To

return to the initial values, click Set default.
6. Click OK to exit the dialog and save the selections.

Working with You can access the Kinetica Population graphs while running an
analysis with or without out covariable(s). For more information,
Kinetica Population see the sections, “Running the Analysis without Covariable(s)”
Graphs and “Running the Analysis with Covariable(s)” in this chapter.
You can view the following types of graphs in Kinetica

Population:
• Population fitting together with individual datasets
• Population fitting with confidence interval together with

individual datasets
• Ycalc versus Vobs
• Wres versus Ycalc
• Res versus Ycalc
• Weighted Residual Distribution
• Parameter Distribution
Yobs versus Ycalc Plot This plot enables you to see the relationship between Yobs
(observed values) and Ycalc (predicted values).
If the fitting is perfect, i.e., Ycalc = Yobs, then the Ycalc versus
Yobs plot is a straight line with unit slope. The x=y line is plotted
as well.

Ycalc v s. Yobs
30
Ycalc vs. Yobs
20
Ycalc()
10
0
0 10 20 30
Yobs()
Figure 11-25. Example - Yobs Versus Ycalc Plot
Wres versus Ycalc Plot This plot enables you to see the relationship between the
Weighted Residual (residual adjusted according to a selected
weighting scheme, e.g. 1, Ycalc, Ycalc2, Yobs, Yobs2) and Ycalc.
The plot takes on a band-like shape, if the weighting scheme is

appropriate. A small residual value suggests a small difference
between Ycalc and Yobs.

Figure 11-26. Example – Weighted Residual vs. Ycalc
Res versus Ycalc Plot This plot enables you to see the relationship between the Residual
and Ycalc prior to a weighting scheme modification.
If the residual is the band-like shaped graph (Res/Ycalc), this

indicates that the selection of homoscedastic residual is
appropriate. If the residual has the shape shown in the following
diagram, then the heteroscedastic residual should be considered.

Figure 11-27. Example – Res vs. Ycalc Plot

Weighted Residual The following graph is an example of a Weighted Residual

Distribution Plot Distribution plot. The ideal situation follows a normal
distribution.
Figure 11-28. Example – Weighted Residual Distribution Plot

Parameter Distribution The parameter distribution plot provides the information on the
Plot evaluation of parameter distribution assumption. In the EM
algorithm, you can assume that the population parameter follows
either normal distribution or log normal distribution. With this
plotting, you can evaluate your assumption.
The following graph is an example of a Normal Distribution plot.

The plot shows an ideal normal distribution. Notice the
symmetrical histogram bars.
Figure 11-29. Example – Parameter Distribution Plot
The following graph is an example of an ideal Log Transformed

Distribution plot.

Figure 11-30. Example - Log Transformed Distribution Plot
Viewing Kinetica Population To view Kinetica population graphs:

Graphs
1. Open the Running Em… dialog, run the iterations, and click
Close. The Individual Graphs dialog appears. For more
information, see the section, “Running the Analysis without
Covariable(s)” or “Running the Analysis with Covariable(s)”
in this chapter.

2. Click Graphic Evaluation. The Select Graphic Evaluation

dialog appears. You can change the number of steps (Nb
Step) to calculate the frequency for parameter distribution.
Figure 11-32. Select Graph Evaluation Dialog
3. All graphs are selected by default. Deselect the check boxes

corresponding to the graphs that you do not want to generate.
4. Click OK to exit the dialog and return to the Individual

Graphs dialog.

5. Click OK to exit the dialog. The following message appears:

“Are you sure you want to close the individual graphs dialog
box?”
6. Click No to return to the Individual Graphs dialog. Click Yes

to view all the graphs in the Gallery item of the Gallery pane.

Population Method In the model validation step, datasets are split into two groups:
one for model building, also called the testing group, and another
Validation for model validation, called the validation group. Kinetica allows
user to validate population model through (1) the parameter
method (Bayesian fit), and (2) the concentration method.
Parameter method For parameter method, the population model validation obtains
(Bayesian fit) the population parameter values and statistics based on the EM
algorithm in Kinetica. These results are then used to run Bayesian
fit (E-step) on the datasets to be validated. The individual
parameters obtained from this step are called Pj,obs.
Case 1 If there are no covariable equations, the deviation of Pj,obs from

the population parameter (Ppred) on the testing group will serve as
the criterion for model validation.
Case 2 If there are covariable equations, the predicted individual

parameter value, called Pj,pred will be obtained from the covariable
equations (obtained from the testing datasets) combining the
covariable information of each subject in the validation dataset
group. Then, the deviation of Pj,obs from Pj,pred will serve as the
criterion for model validation.
Concentration method The concentration method uses the parameter values from testing
dataset to predict the concentrations for individuals in the
validation dataset group, and the 95% confidence interval. The
concentration obtained from the prediction is called Ci,j,pred. The
measurement of the concentration in the validation group is
called Ci,j,obs.

Case 1 If there are no covariable equations, the parameter values

obtained from the testing group will be used to predict the
concentration of the validation group (expressed as mean and
95% confidence interval of the mean). These values will be
compared with the observed concentration of the validation
datasets. The 95% confidence interval will be calculated based on
inter-individual variability and intra-individual variability
obtained from the results of the testing group.
Case 2 If there are covariable equations, the predicted individual

concentrations for those subjects who belong to the validation
dataset group can be calculated using the predicted individual
parameters, Pj,pred (as shown in the parameter method, case 2).
Then, the predicted concentration for each individual in the
validation group is calculated, along with its 95% confidence
interval. The predicted individual concentration will be plotted
against the observed concentration for the validation dataset
group.
Running Population Validation For this example, we shall use a template with stored data for
Using Parameter Method population methodology.
appears.
2. Select the Population tab.
3. Click on the PopFitMicroIVBolus1comp icon and select the

Open with Data check box. Click OK.

Figure 11-33. New Analysis Dialog – Population Tab
4. Access population method validation by clicking the

following toolbar menu: Population | Validation | Validation
Setup.
Figure 11-34. Population Validation Menu Options
5. Population method validation allows the user to choose the

population model the user wishes to validate by either
entering parameters manually or run EM, then validate. For
this example, select Run EM, then validate. The user has the
option of selecting model building datasets manually or
model building datasets by randomization. In the drop-down

menu box, choose Select model building datasets by

randomization. If a population EM model is previously set-
up, click Enter parameters manually and go to step 16.
Figure 11-35. Model Validation Dialog
6. Input 400 in the Number of model building datasets box.

The remaining datasets will be used for validation. The
default setting is the maximum number of datasets to be used
for model building.
7. To view the subjects used for validation, click Randomize.

The user may add or remove subjects manually by Ctrl-
clicking on the subjects. Then click OK.
Figure 11-36. Select Model Building Datasets Dialog

8. To view the other option, choose Select model building

datasets manually in the drop-down menu box. Notice that
both boxes for the number of model building datasets and
number of model validating datasets are now shaded. Click
Dataset button to choose the subjects for model building.
Figure 11-37. Model Validation Dialog
9. Select subjects 1 to 330 by shift-click. Click OK.
Figure 11-38. Example – Subject Selection
10. The boxes for the number of model building datasets and
number of model validating datasets are automatically
calculated for the Model Validation dialog. Click Next.

11. Set initial parameter values and run population analysis

identical to those for population models. (See the Running an
Example Template (PopFitMicroIVBolus1comp single dose
section)).
Figure 11-39. Set Initial Parameter Values Dialog
12. After running the population analysis, the Validation Setup

allows the user to choose whether to run EM with covariables
immediately, later or not to run EM with covariables. Since
this example does not contain demographic value, select Do
not run EM with covariables. Click Next.
Figure 11-40. Validation Setup Dialog

13. Kinetica will prompt the user whether to save the previous
run. Click Yes.
Figure 11-41. Save EM Results Confirmation Dialog
14. Save the file as PracticePopValidation. Click Save.
15. The dialog: Validation setup is complete. You can now run
validation appears. Click OK.

Figure 11-43. Validation Complete Dialog
16. Start validation by clicking Population | Validation | Run

Validation…
Figure 11-44. Validation Menu Options
17. Run validation prompts the user to choose the population

method and provides the choice of whether to use the
parameter estimates or the time-concentration data for
validating the remaining datasets. Select
PopFitMicroIVBolus1comp and Parameter for Population
Method and Validation Method drop-down menus. Click
Run.

Figure 11-45. Run Validation Dialog
18. Bayesian Fitting dialog appears. Click Start. When the fitting
is finished, click Close.
Figure 11-46. Bayesian Fitting Dialog
19. Individual graphs dialog allows the user to view the datasets
used for validation and selection for report set-up, datasets

used for the validation process, export to Word, export to

gallery, number of columns in the gallery, level of confidence
interval . Click OK.
20. Kinetica verifies whether the user wants to close the

individual graphs dialog box. Click Yes.
Figure 11-48. Close Confirmation Dialog
21. Kinetica prompts user whether to save the results. Click Yes.

Figure 11-49. Kinetica Save Dialog
22. The graphs sent to the gallery include: Bayesian parameter

prediction versus population estimate, confidence interval of
the individual estimate and confidence range for the
population estimate, and the distributions of weighted
residual errors and parameters.
Figure 11-50. Example – Graph Gallery

Running Population For this example we will use the template containing covariables.
Validation Using
Concentration Method 1. Select Open from the File menu. Within the Data folder,
with Covariable open the EMValidateConc file.
2. Access population method validation by clicking the

following: Population > Validation > Validation Setup.
3. Select Run EM, then validate. Choose Select model building

datasets by randomization.
4. Input 15 in the Number of model building datasets box.

View the subjects used for validation by clicking Randomize.
5. Close the Select Model Building Datasets dialog. Click Next

on the Model Validation dialog.
6. Set initial parameter values and run population analysis

identical to those for population models.
7. Select Run EM with covariables now. Click Next.
Figure 11-51. Validation Setup Dialog
8. Save the EM results as EMValidateConcCovar.
9. The following dialog appears. Click OK.

Figure 11-52. Kinetica EM with Covariables Dialog
10. Another dialog will ask whether the user want to run
Validation from the last one. Click Yes.
Figure 11-53. Kinetica Validation Dialog
11. Add BW as a covariable of Volume and Kel as a power

function.

12. Save the covariable model.
Figure 11-55. Kinetica Save Dialog
13. Run the model with covariable similar to running a

population model.
14. Save the new EM result as EMValidateConcCovar2.
15. Run validation by clicking Population > Validation > Run

Validation.

16. Select Concentration under the Validation Method drop-

down menu. Make sure that Run with Covariables check box
is selected. Click Run.
17. Click OK on the Individual Graphs dialog.

18. Save results and view data under All Variables in the Study
pane. The individual worksheet under Dataset pane contains
Ycalc, IDeviation, and RMS_Error columns. The Yobs versus
Ypred plot is sent to the gallery.

Working with The Population Designer enables you to generate and save a
symbolic population model. Unlike Kinetica Designer,
Population Designer Population Designer enables you build a model with multiple
dose. In all other aspects, the procedure for using the Population
Designer is identical to the procedure provided for the Kinetica
Designer. For more information, see the section, “Kinetica
Designer” in chapter, “Working with Methods and Models.”
To create a symbolic population model:
1. Select Designer then Population from the Tools menu. The

Population Designer appears.
Figure 11-58. Population Designer Dialog
2. Double click one of the icons on the toolbar and click

anywhere in the workspace area. The Multidose dialog
appears.
• To create a model for single dose, click Cancel.
• To create a model for multiple doses, enter the

appropriate worksheet, dose column, and dose time
column for the symbolic model and click OK.

Figure 11-59. Multidose Dialog
4. To continue using the Population Designer, see the section,

“Kinetica Designer” in the chapter, “Working with Methods
and Models.”

Exporting Data to You have the option to export population data to Microsoft
Word from the Individual Graphs dialog. In order to export the
Microsoft Word information successfully, ensure that you specify Word as the
default destination for information in the Report Setup dialog
before you run an analysis with or without covariables. You can
access the Report Setup option from the toolbar, by selecting
Report Setup from the File menu, or by clicking Report Setup in
the Individual Graphs dialog. For more information, see the
chapters, “Configuring Kinetica” and “Importing and Exporting
Data.”
Note Kinetica uses the Normal template that is loaded by

default in your version of Microsoft Word. The format of the
exported results depends on how your styles are defined in your
Normal template. The tabulation may look skewed when you
export to Word. Adjust the tab stops in Word to reorganize the
data. ▲
For more information related to the Individual Graphs dialog, see

the section, “Running the Analysis without Covariable(s)” in this
chapter.
The following information is exported to Microsoft Word from

the Individual Graphs dialog:
• The date the report was generated
• Population method name
• Selected error model
• Selected datasets included in the report
• Input columns
• Input study parameters
• Parameter initialization values
• CV initialization values
• Fitting results

• Population parameters
• Population CV
• Population variance
• Statistics for SPPE
• Standard error of estimate
• Parameters criteria results
• Elapsed time for the EM algorithm and the number of

iterations
• Warnings associated with the analysis
• Selected graphs in Graphical Evaluation (also exported to the

gallery)
• Population CI (Predicted or Individual)
• Covariable equations (analysis with covariables only).
To export data to Microsoft Word:
1. Open the Running Em… dialog, run the iterations and click
Close. The Individual Graphs dialog appears. For more
information, see the section, “Running the Analysis without
Covariable(s)” or “Running the Analysis with Covariable(s)”
in this chapter.
2. Select the graphs you want to generate (see the section,

“Working with Kinetica Population Graphs” in this chapter).
3. Click OK to exit the Individual Graphs dialog. The following

message appears: “Are you sure you want to close the
individual graphs dialog box?”
4. Click Yes to view all the graphs in the Gallery item of the
Gallery pane and to export data to Word.

Notes

12. Performing Statistical
Analysis
The following chapter provides information and instruction on
performing statistical analysis within Kinetica. The statistics
menu in Kinetica contains basic descriptive statistics, parametric
and non-parametric statistical evaluation, average and individual
bioequivalence, including balanced and incomplete block designs.

Performing Statistical Analysis
Statistical Analysis There are no templates in Kinetica for statistical analysis.

Generally, you can perform a statistical analysis after
in Kinetica pharmacokinetic analysis without using a statistical template. The
statistical analysis examples contained in this chapter were
obtained by using options selected from the Statistics item on the
main menu. The statistical tests used are not methods and do not
appear in the Methods view of the Study or Dataset panes. We
have supplied several kdb files, one for each statistical test, to
explain how to use the test and what type of data should be used.

ANOVA You can perform an analysis of variance (ANOVA) calculation in

four different ways within Kinetica:
• One-way analysis
• Two-way analysis
• Three-way analysis
• Replicate analysis.
Parallel studies can be viewed as one-way analysis of variance or

one-factor experiments. In a one-factor experiment observations
are taken for p independent groups with q observations in each
group (i.e. there are p treatments each with q repetitions).
Crossover studies are a little different. There are many types of

crossover studies, but we will focus the analysis on the 2-way and
3-way crossover studies.
A 2-way crossover study, also known as a two-factor experiment,

is a two-variable experiment. This means that observations are
taken for p independent groups and q blocks, such that there is
one experimental value that corresponds to each pi (treatment i, i
= 1…p) qj (block j, j=1..q). In other words, if we view the results
as a table (pxq) there is one experimental value corresponding to
every treatment (p) and block (q).
A 3-way crossover study also known as a three-factor experiment,

is a three-variable experiment. This means that observations are
taken for p independent groups, q blocks, and r sequences, such
that there is one experimental value that corresponds to each pi
(treatment i, i = 1…p) qj (block j, j=1..q) and rk (sequence k,
k=1…r). In other words, if we view the results as a table (3-D this
time with pxqxr) there is one experimental value corresponding to
every treatment (pi) in block (qj) in the sequence (rk).
A replicate study involves a subject receiving both the test and the
reference product in more than one period. For example, in a
fully replicated study the distribution would appear like the
following example:

Subject Period 1 Period 2 Period 3 Period 4 Sequence
S1 R T T R 1
S2 T R R T 2
ANOVA n-Way Dialog The ANOVA test can be performed in the ANOVA n-way
dialog. This dialog is accessed by selecting ANOVA from the
Statistics menu.
Figure 12-1. ANOVA n-way dialog
The items that appear in the dialog are described in the following
table.

Item Format Description
Number of ways Enter a number between 1 and 4

depending of the number of factors in
your analysis. The program will then
activate the column lists according to
your entry.
Data column Select the data on which you want to

perform the ANOVA analysis.
(for example: AUC, Cmax, Tmax, T1/2, etc).
Treatment column Select the Treatment field from the list.

Generally, the treatment effect is always
analyzed.
2, 3 and 4-way Select the Data corresponding to the

columns nature of your factor(s), for example,
Subject, Center, etc).
Log transformation Select this option to log-transform your

for data data during the ANOVA analysis. Do
not select this option if your data has
already been log-transformed or if you do
not want to log-transform your data.
Note: Kinetica enables the entry of alpha

and numeric values for all analysis fields
When an ANOVA analysis is complete a table of results is written

in the Study Info view of the Study pane. For this particular test
the organization of this table always appears as follows:
Source df SS MS F p
(Degree of (Sum of (Mean (Fischer (Probability

freedom) Squares) Square) test) value)
Total 1 2 3 4 *5
Treatment 6 7 8 9 *10

Source df SS MS F p
(Degree of (Sum of (Mean (Fischer (Probability

2 Way 11 12 13 14 *15
3 Way 16 17 18 19 *20
4 Way 21 22 23 24 *25
Error 26 27 28 29 *30
*In the ANOVA Table, the value of p for every effect is compared to 0.05 (α = 5%).
Kinetica computes and outputs a conclusion according to the following rules:
• If p > 0.05 the difference is not significant, so output the

symbol is NS
• If p < 0.05 the difference is significant, so output the symbol

is ***.
Note The p values are never generated for the Error and Total
fields. The root mean square error is calculated by Sqrt (MS
error), and the C.V. is calculated by (number of data * Root
Mean Square Error) / ∑ x . ▲
The equations used to calculate the data in the previous table (i.e.
1, 2, 3) are listed in the following table:
Note For each of the data x, C = (∑ x) 2
where N = total
N
number of data. ▲
Point Equation Used
1 Total number of data – 1
2 ∑x 2
i - nC
3 SS total / df (total)

Point Equation Used
4 No calculation is made and no output generated
6 (Number of treatments) –1
7 2
⎛ ni ⎞
⎜ ∑ x i ( j)⎟
⎝ j =1 ⎠
∑
i =1 ni
-C
8 SS treatment / df (treatment)
9 MS treatment / MS error
10 (Number of ways 2) –1
11 2
⎛ ni ⎞
⎜ ∑ x i ( j)⎟
⎝ j =1 ⎠
∑
i =1 ni
-C
12 SStwo way / df (2 way)
13 MStwo way / MS error

Point Equation Used
15 2
⎛ ni ⎞
⎜ ∑ x i ( j)⎟
⎝ j =1 ⎠
∑
i =1 ni
-C
16 SS 3 way / df (3 way)
17 MS 3 way / MS error
19 2
⎛ ni ⎞
⎜ ∑ x i ( j)⎟
⎝ j =1 ⎠
∑
i =1 ni
-C
20 SS 4 way / df (4 way)
21 MS 4 way / MS error
22 df (total) - ( df treatment + dftwo way + df 3 way + df

4 way)
23 SS (total) - ( SS treatment + SStwo way + SS 3 way +

SS 4 way)
24 SS error / df (error)

Presentation of Partial The descriptive statistics are computed with the following
Descriptive Statistics equations:
Mean:
Mean = ∑ data / number of data
Standard Deviation:
∑ x − (∑ x )
2
2
/ Number of data
SD =
Number of data - 1
Standard Error Mean:
SD
SEM =
Number of data
GeoMean and GeoSD:
The geometric standard deviation describes how spread out are a

set of numbers whose preferred average is the geometric mean. If
the geometric mean of a set of numbers {A1, A2, ... , An} is
denoted as µg, then the geometric standard deviation is computed
as:
∑
n
(ln Ai − ln µ g ) 2
σ g = exp i =1
n −1
where µg is the geometric mean, which is calculated as

n A1 A2 A3 ... An .
The root mean square error is the square root of the mean square
error.
The power of the test is the statistical power, which is defined as

the complement of type II error.

1 – Power is the Type II error, often designated as β and is

defined as the probability of accepting the null given that the
alternative is true.
Minimum detectable difference (MDD) evaluates how different

observed values of a multimetric index must be in order to be
significantly different.
Confidence Intervals Kinetica gives you the option to compute the reference
confidence intervals in accordance with the regulatory agency
guidelines. These also provide a further option for considering
whether the data was log-transformed or not.
Option Regulatory Agency
FDA Europe
No Log [0.8 - 1.2] [0.7 - 1.3]

Transformation
Log Transformation [0.8 - 1.25] [0.7 - 1.43]
Kinetica computes a 90% standard confidence interval t = t (2 *

alpha - df error) where:
Test = New formulation
Ref = Reference formulation.

Log Transformation Option This is used when the model is multiplicative and a confidence
interval is obtained around the difference between two
formulations. If requested, a Log-Transformation is computed
using the following rule:
MSerror × 2
If I = (MeanTest - MeanRef) - t
Number of data for Ref
and
MSerror × 2
J = (MeanTest - MeanRef) + t
Then
The lower CI limit = eI and the upper CI limit = eJ.
No Log Transformation Option The no log transformation option is used when the model is
additive and a confidence interval is obtained around the ratio of
two formulations. If requested, a No Log-Transformation is
computed using the following rule:
MSerror × 2
Mean Test - t
The lower CI limit =
Mean Ref
and
MS error × 2
Mean Test + t
The upper CI limit =
Mean Ref
Conclusion on the Confidence Kinetica compares the calculated CI with the reference CI. If the
Intervals calculated CI is inside the reference CI, a message is displayed in
the Study Info view of the Study pane stating “Can conclude
equivalence”. If the calculated CI is outside the reference CI, a
message is displayed stating “Cannot conclude equivalence.”

Two One-Sided t-Tests for The Schuirmann’s test is used in the case where there is a
Factor: Schuirmann's Test confidence interval around the difference between two
formulations. Two unilateral t-tests are calculated as follows:
t = t (0.05 - df error)
d = MeanTest - MeanRef
2 × MS error
S=
Number data in Ref
C1 = ln (the lower reference CI limit)
C2 = ln (the upper reference CI limit)
t1 =
C2 − d
t2 =
S
The smallest value between t1 and t2 is the lower t and the other
is the upper t. A conclusion is then computed using the following
rules:
1. If t (lower) ≥ t and t (upper) ≥ t then output the message can

conclude equivalence.
2. If t (lower) ≤ t or t (upper) ≤ t then output the message

cannot conclude equivalence.

Example of ANOVA Two-Way In this example, six patients were treated with three formulations:
Analysis A, B and C (where C was the Reference formulation, and A and
B were the New formulations). Cmax measurements were taken for
every patient and formulation.
You can enter numbers or letters in the Subject and Treatment

columns. Initials or names of patients, and names of formulations
can be entered. There is no obligation to code the patients and
formulations by numbers (1, 2, 3, etc…).
The example given is an ANOVA two-way analysis. The data is at

Cmax.
To complete an ANOVA two-way analysis:
2. Navigate to the Program Files\Kinetica\Example\Statistics

directory, select the Anova.kdb file, and click Open.

containing sample data from Anova.kdb:

Figure 12-3. Kinetica Study pane showing Anova.kdb
4. Select ANOVA from the Statistics menu. The ANOVA n-

way dialog appears.
5. In the Number of Ways field, select 2 from the list. The first
three list boxes (Data Column, Treatment Column and 2
Way Column) are activated.
6. Select data from the Data Column list box, Treatment from
the Treatment Column list box, and Subject from the 2 Way
Column list box.
7. Select either the Ln Transform of data or Log10 Transform of

Data check box.

8. Select the Confidence Intervals check box. This activates the

Reference Level and Test Level fields.
9. Enter A in the Reference Level field and B in the Test Level

field.
10. Select the Log option [0.8 - 1.25] in the Reference

Confidence Intervals area of the dialog.
11. Select the Two One-Sided t-tests for Factor check box. This
activates the Reference Level and Test Level fields.
12. Enter A in the Reference Level field and B in the Test Level
field. The ANOVA dialog should now appear as follows:
Figure 12-4. ANOVA n-way Dialog
Note The data column contains the Cmax values. ▲

You can view the results of the ANOVA analysis, the Confidence
Interval and the Schuirmann’s two one-sided test in the Study
Schuirmann’s two one-sided test: Let µd be the mean difference of

the bioavailabilities, such as AUC and Cmax, of the object drug
between the first and last periods depicted as above, θL denotes
the lower no-effect boundary, and θU denotes the upper no-effect
boundary, then the objective of the drug-drug interaction in a
fixed-sequence design can usually be tested in the following two
one-sided hypotheses:
Null hypothesis (H0): µd ≤θL or µd ≥θU
Alternative hypothesis (Ha): θL <µd <θU
Assuming logarithmically transformed data would be normally

distributed, then H0 is rejected at significance level 〈and no drug-
drug interaction is concluded if 100 (1-2α) % CI of the mean µd
is entirely within (θL, θU ), otherwise H0 fails to be rejected. The
choices of no-effect boundaries depend on the specific drugs
involved in the study.

Latin Square When you have a cross-over design (Latin Square), Kinetica
makes a distinction between a Latin Square with two
formulations and a Latin Square with greater than two
formulations.
Latin Square - Two The Latin Square option enables you to perform an analysis on a
Formulations conventional two-treatment, two-period randomized crossover
design. Following the most recent FDA guidelines for
bioequivalence studies, the Subject effect nested in sequence, the
Sequence effect, and the Period effect are all considered by the
Latin Square ANOVA.
The conditions for use are a crossover design limited to two

formulations with no missing values.
Latin Square 2 Formulations The Latin Square with two Formulations test can be performed
Dialog using the Latin Square 2 Formulations dialog. This dialog is
accessed by selecting Latin Square with two Formulations from
the Statistics menu.
Some of the main items that appear in the dialog are described in
Object Description
Data column Select the Data on which you want to

perform the ANOVA analysis (for example:
AUC, Cmax, Tmax, T1/2, etc).
Subject column Select the Subject field from the list
Treatment Select the Treatment field from the list.

column Generally, the treatment effect is always
analyzed.
Sequence Select the Sequence field from the list

column
Log See the section, “Log Transformation

Transformation Option” in this chapter

Object Description
Confidence See the section, “Confidence Intervals” in

Intervals this chapter
Two-One-Sided See the section, ”Two One-Sided t-Tests for

t-tests for factor Factor: Schuirmann's Test” in this chapter
Presentation of ANOVA Table for When an ANOVA table is complete for Latin Square testing, a
Latin Square Testing table of results is written in the Study Info view of the Study
pane. For this particular test the organization of this table always
appears as follows (in this example, T1/2 were the data selected):
df SS MS F p
Source (Degree of (Sum of (Mean (Fischer test) (Probability value)

freedom) Squares) Square)
Period 1 2 3 4 *
Subject (Seq) 5 6 7 8 *
Formulation 9 10 11 12 *
Sequence 13 14 15 16 *
Error 17 18 19 20
Total 21 22 23 24
*In the ANOVA Table, the value of p for every effect is compared to 0.05 (α = 5%), and Kinetica computes and outputs
a conclusion according to the following rules:
• If p > 0.05 then the difference is not significant, so output the

symbol NS
• If p < 0.05 then the difference is significant, so output the

symbol ***.

fields. The Root Mean Square Error is calculated by Sqrt (MS
error) and the CV is calculated by (number of data * Root Mean
Square Error) / ∑ x . ▲
The equations used to calculate the data that appear in the

preceding table (i.e. 1, 2, 3, etc.) are listed in the following table.
Note For each of the data x, C =

(∑ x ) 2
where N = total
N
number of data. ▲
Point Equation Used
1 (number of periods) –1
2 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C
3 SS period / df (period)
4 MS period / MS error
5 This “Subject” effect is nested in the Sequence.
(number of subjects) - (number of sequences)
6 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C
7 SS subject / df (subject)
8 MS subject / MS error
9 (number of formulations) -1

Point Equation Used
10 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
–C
11 SS formulation / df (formulation)
12 MS formulation / MS error
13 (number of sequences) –1
14
⎡ ⎛ nj ⎞ ⎤
2
numbersequences ∑ k
⎡ 2
⎤ ⎢ ⎜ x ( j )⎟ ⎥
⎛ n ⎞
⎢ ⎜ ∑ x i ( j) ⎟ ⎥ ⎢ ⎝ ⎠ ⎥
⎢
⎢∑
⎝ j= 1 ⎠ ⎥
⎥ -
⎢ ∑ n ⎥
⎢ i=1
ni
⎥
⎢ j =1 j ⎥
⎢ ⎥ ⎢ ⎥
⎣ ⎦ ⎣ ⎦
In fact, the calculation of the 2nd term means:
number sequences
⎛ mean for 1 sequence • number of data in this sequence ⎞
∑j= 1
⎜
⎝ number of data in this sequence
⎟
⎠
15 SS sequence / df (sequence)
16 MS sequence / MS error
17 df (total) - ( df formulation + df subject + df period + df sequence)
18 SS (total) - (SS formulation + SS subject + SS period + SS sequence)
20 no calculation is made and no output generated
21 (total number of data) –1
22 ∑x 2
i –C

Point Equation Used
Mean:
Standard Deviation:
∑ x − (∑ x )
2
2
/ Number of data
SD =
Number of data - 1
Standard Error of the Mean:
SD
SEM =
Number of data
GeoMean and GeoSD:

the geometric mean of a set of numbers {A1, A2, ... , An} is
denoted as µg, then the geometric standard deviation is computed
as:
∑
n
σ g = exp i =1
n −1
where µg is the geometric mean, which is calculated as:
n A1 A2 A3 ... An
.

Example of Latin Square with In this example, six patients were treated with two formulations A
Two Formulations and B in a cross-over design with two sequences, AB and BA. T1/2
was calculated for every patient, formulation and sequence.

The example below is a Latin Square analysis without log-

transformation of data.
1. In Kinetica select Open from the File menu. The Open a

Kinetica File dialog appears. By default, the Data subdirectory
is displayed.

directory, select the Latin Square 2 Formulations.kdb file, and
click Open.

containing only raw data:

Figure 12-5. Kinetica Study Pane showing Latin Square 2

Formulations.kdb
4. From the Statistics menu select Latin Square, then Two

Formulations. The Latin Square 2 Formulations dialog
appears.
5. Select T1/2 from the Data Column list box, Subject from the
Subject Column list, Treatment from the Treatment Column
list, and Sequence from the Sequence Column list. The dialog
should appear as below.

Figure 12-6. Latin Square 2 Formulations dialog
You can view the results of the ANOVA analysis for Latin Square
design with two formulations in the Study Info view of the Study
pane.
Latin Square - Greater In the Latin Square design with greater than two formulations,
Than Two Formulations you can select:
1. A Latin Square design with more than one square, or
2. A simple Latin Square design.
Latin Square - Greater Than Two The conditions for use are a cross-over design, no missing values,
Formulations with Multiple where all the possible sequences are represented and the data is
Square Design limited to three formulations. For example, for three studied
formulations A, B and C, you must have the sequences ABC,
BCA, CAB, ACB, BAC and CBA.

The Subject effect nested in Sequence, and the Sequence effect

are not considered by the Latin Square ANOVA. If you choose
this option, you must select the More Than One Square check
box in the Latin Square n Formulations dialog.
Latin Square n Formulations The Latin Square with Greater than two Formulations test can be
Dialog performed using the Latin Square n Formulations dialog, accessed
by selecting Latin Square then Two Formulations from the
Statistics menu. However, now you will see the More Than One
Square check box enabled. This option enables you to choose
between the multiple square design or the basic single square
design. This is the main difference between the Latin Square n
Formulations dialog and the Latin Square 2 Formulations dialog.
Presentation of ANOVA Table for Latin Square Three

Formulations (Multiple Square Design):
When an ANOVA table is complete for Latin Square testing, a

table of results is written in the Study Info view of the Study
pane. For this particular test, the organization of this table always
appears in the following table (in this example, T1/2 was the data
selected).
df SS MS F p
Source (Degree of (Sum of (Mean (Fischer (Probability

Period 1 2 3 4 *
Subject 5 6 7 8 *
Error 13 14 15 16
Total 17 18 19 20
*In the ANOVA Table, the value of p for every effect field is compared to 0.05 (α = 5%), and
Kinetica computes and outputs a conclusion according to the following rules:

symbol NS.


symbol ***.
fields. ▲
The Root Mean Square Error is calculated by Sqrt (MS error)

and the CV is calculated by (number of data * Root Mean Square
Error) / ∑ x .

ANOVA table above (i.e. 1, 2, 3, etc.) are listed in the following
table.
For each of the data x:
C=
(∑ x ) 2
where N = total number of data.
Point Equation Used
2 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C
5 (number of subjects) – 1

Point Equation Used
6 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C
9 (number of formulations) -1
10 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C
13 (df total) - ( df formulation + df subject + df period)
14 (SS total) - ( SS formulation + SS subject + SS period)
18 ∑x 2
i -C

Mean:
Standard Deviation:
∑ x − (∑ x ) / Number of data
2 2
SD =
Number of data - 1
SD
SEM =
Number of data
GeoMean and GeoSD:

the geometric mean of a set of numbers {A1, A2, ... , An} is denoted
as µg, then the geometric standard deviation is computed as:
∑
n
σ g = exp i =1
n −1
n A1 A2 A3 ... An .
Example of Latin Square Three In this example, six patients were treated with three formulations
Formulations with Multiple A, B and C in a cross-over design with six sequences: ABC, BCA,
Square Design CAB, ACB, BAC and CBA. T1/2 was calculated for every
patient, formulation and sequence.



formulations by numbers (i.e. 1, 2, 3).
The example below is a Latin Square analysis without log-

1. Load Kinetica.
By default, the Data subdirectory is displayed.
3. Select the LatinSquare2Formulations.kdb file, found in the

Program Files\Kinetica\Example\Statistics directory, and click
Open.

the program:
Figure 12-7. Latin Square Multiple Squares Dialog

5. Select Latin Square then Two Formulations from the

Statistics menu. The Latin Square n Formulations dialog
appears.
Figure 12-8. Latin Square n Formulations Dialog
Note The More than one square check box is now enabled.
The data column contains the T1/2 values. ▲
6. Select data from the Data column list box, Subject from the
Subject column list box, Treatment from the Treatment
column list box, Sequence from the Sequence column list
box. Finally select the More Than 1 Square checkbox. The

Figure 12-9. Latin Square 3 Formulations Only Dialog
Note The title of the dialog has changed, indicating that

with the multiple square design selected you cannot have
more than three formulations. ▲
7. Do not select any other options from the dialog. Click OK to

exit the dialog and generate the report.
design with three formulations and more than one square in the
Study Info view of the Study pane.

Latin Square n If you select this option, do not select the More Than One
Formulations with Single Square check box. With this design you can have n formulations
(as many as you require). All the possible sequences are not
Latin Square Design
represented. The conditions for use are a cross-over design, no
missing values, where the number of formulations must be equal
to the number of sequences.
Following the last FDA guidelines for bioequivalence studies, the

Subject effect nested in sequence, the Sequence effect, and the
Period effect are all considered by the Latin Square ANOVA.
The Latin Square with n Formulations and Single Latin Square

Design test can be performed in the Latin Square n Formulations
dialog.
Latin Square n Formulations This dialog is accessed by selecting Latin Square then Two
Dialog Formulations from the Statistics menu.

Presentation of ANOVA Table for When an ANOVA table is complete for Latin Square testing, a
Latin Square n Formulations table of results is written in the Study Info view of the Study
pane. For this particular test the organization of this table always
appears as follows (in this example T1/2 was the data selected):
df SS MS F p
Source (Degree of (Sum of (Mean (Fischer test) (Probability value)

freedom) Squares) Square)
Period 1 2 3 4 *
Subject (Seq) 5 6 7 8 *
Sequence 13 14 15 16 *
Error 17 18 19 20
Total 21 22 23 24
*In the ANOVA Table, the value of p for every effect field is compared to 0.05 (α = 5%), and Kinetica computes and
outputs a conclusion according to the following rules:

symbol NS.

symbol ***.
fields. The Root Mean Square Error is calculated by Sqrt (MS
error) and the CV is calculated by (number of data * Root Mean
Square Error) / ∑ x . ▲

preceding table (i.e. 1, 2, 3) are listed in the following table.

C=
(∑ x ) 2
Point Equation Used
2 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C
5 This subject effect is nested in the Sequence
(number of subjects) - (number of sequences)
6 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C
9 (number of formulations) –1
10 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C

Point Equation Used
13 (number of sequences - 1)
14
⎡ ⎛ nj ⎞ ⎤
2
numbersequences ∑ k
⎡ 2
⎤ ⎢ ⎜ x ( j )⎟ ⎥
⎛ n ⎞
⎢ ⎜ ∑ x i ( j) ⎟ ⎥ ⎢ ⎝ ⎠ ⎥
⎢
⎢∑
⎝ j= 1 ⎠ ⎥
⎥ -
⎢ ∑ n ⎥
⎢ i=1
ni
⎥
⎢ j =1 j ⎥
⎢ ⎥ ⎢ ⎥
⎣ ⎦ ⎣ ⎦
In fact, the calculation of the 2nd term means:
number sequences
⎛ mean for 1 sequence • number of data in this sequence ⎞
∑
j= 1
⎜
⎝ number of data in this sequence
⎟
⎠
15 SS sequence / df (sequence)
16 MS sequence / MS error
17 df (total) - ( df formulation + df subject + df period + df sequence)
18 SS (total) - (SS formulation + SS subject + SS period + SS sequence)
21 (total number of data - 1)
22 ∑x 2
i -C

Mean:
Standard Deviation:
∑ x − (∑ x)
2
2
/ Number of data
SD =
Number of data - 1
SD
SEM =
Number of data
GeoMean and GeoSD:

∑
n
σ g = exp i =1
n −1
n A1 A2 A3 ... An .
Example of Latin Square n Formulations with Single Square

Design
In this example, six patients were treated with three formulations

A, Band C in a cross-over design with three sequences: ABC,
BCA and CAB. T1/2 was calculated for every patient, formulation
and sequence.


The example given is a Latin Square analysis without log-

To complete a Latin Square analysis with Single Square design:
1. Load Kinetica.
3. Select the LatinSquareNFormulations.kdb file, found in the

Program Files\Kinetica\Example\Statistics directory, and click
Open.
4. Select the Study pane. The Study pane appears as follows,

the program:

Figure 12-10. Latin Square N Formulations Dialog
5. Select Latin Square then Two Formulations from the

Statistics menu. The Latin Square 2 Formulations dialog
appears:

Figure 12-11. Latin Square 2 Formulations Dialog
Note The More than 1 square check box is now activated.

The data column contains the T1/2 values. ▲
6. Select data from the Data column list box, select Subject from
the Subject column list box, select Treatment from the
Treatment column list box, and select Sequence from the
Sequence column list box. Do NOT select the More than 1
square check box. The dialog appears as follows:

Figure 12-12. Latin Square n Formulations Dialog
Note The title of the dialog has changed, indicating that

with Multiple Square Design selected you can not have more
than three formulations. ▲
7. Select no other options from the dialog. Click OK to exit the

dialog and generate the report.
design with three formulations and one square in the Study Info
view of the Study pane.

Incomplete Block Incomplete block refers to statistical designs in which the block is
complete (i.e. all the treatments are represented in a sequence),
but not balanced (i.e. all the possible sequences are not
represented). The conditions for use are:
1. The number of formulations must be equal to the number of

periods, and
2. The number of formulations must be less than the number of

sequences.
Incomplete Block Dialog The Incomplete Block test is performed using the Incomplete
Block dialog. This dialog is accessed by selecting Incomplete
Block from the Statistics menu.
Presentation of ANOVA Table for When an ANOVA table is complete for Incomplete Block
Incomplete Block testing, a table of results is written in the Study Info view of the
Study pane. For this particular test the organization of this table
always appears as follows:
df SS MS F p
Source (Degree of (Sum of (Mean (Fischer (Probability

Period 1 2 3 4 *
Subject 5 6 7 8 *
Error 13 14 15 16
Total 17 18 19 20
*In the ANOVA Table, the value of p for every effect is compared to 0.05 (α = 5%), and Kinetica
computes and outputs a conclusion according to the following rules:

symbol NS


symbol ***.
Note The p values are not generated for the Error and Total
fields. ▲
The Root Mean Square Error is calculated by Sqrt (MS error)

and the CV is calculated by (number of data * Root Mean Square
Error) / ∑ x .

preceding table (i.e.1, 2, 3, etc.) are listed in the following table:
( x)
C= ∑
2
Point Equation Used
2 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C
5 (number of subjects) – 1
6 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C

Point Equation Used
9 (number of formulations) –1
10 2
⎛ n ⎞
⎜ ∑ x i (j)⎟
⎝ j=1 ⎠
∑
i =1 ni
-C
13 (df total) – ( df formulation + df subject + df period)
14 (SS total) – (SS formulation + SS subject + SS period)
18 ∑x 2
i –C

Mean:
Standard Deviation:
∑ x − (∑ x)
2
2
/ Number of data
SD =
Number of data - 1
SD
SEM =
Number of data
GeoMean and GeoSD:

∑
n
σ g = exp i =1
n −1
n A1 A2 A3 ... An .
Example of Incomplete Block In this example, four patients were treated with three
formulations A, B and C with four sequences: BAC, CBA, ACB
and BCA. Tmax was calculated for every patient, formulation and
sequence.



The example given is an Incomplete Block analysis without log-

1. Load Kinetica.
dialog appears.

directory, select the Unbalanced Block.kdb file and click
Open.

the program:
Figure 12-13. Kinetica Study Pane with file “Unbalanced

Block.kdb” loaded

5. Select Incomplete block… from the Statistics menu. The

Incomplete Block dialog appears.
Figure 12-14. Incomplete Block Dialog
6. Select data from the Data column list box, select Subject from
the Subject column list box, Treatment from the Treatment
column list box and Sequence from the Sequence column list
box.
Note The data column contains the Tmax values. ▲
7. Select no other options from the dialog. Click OK to exit the

dialog and generate the report.
You can find the results of the ANOVA analysis for Incomplete
Block in the Study Info view of the Study pane.

Kruskall-Wallis Test Kinetica enables you to access a non-parametric test, Kruskall-

Wallis. The Kruskall-Wallis test is a non-parametric test
equivalent to a one-way analysis of variance.
The conditions for use are where the data and groups are
independent of each another.
Hypothesis of the test is where:
Ho – Signifies no difference between means
H1 – Signifies a difference between means.
We sort the data by ascending order, noting the group to which

each item belongs.
12 Si2
H = ∑ − 3( N + 1)
N(N + 1) i ni
where:
H = Criteria in the Kruskall-Wallis test
N = Total number of data
ni = Number of data for each group (1, 2,…,i)
Si = Sum of ranks of data for each group (1, 2,…,i)
χ2( 0,95−(number of groups−1) )
A comparison between H and χ 2 is made, and the following

rules are applied:
If H < χ 2 then accept Ho (difference between means is not

significant).
If H > χ 2 then reject Ho (difference between means is

significant).

In the ex-aequo case the data have a rank equal to the mean of
their own ranks and H is obtained by:
12 Si2
∑ − 3( N + 1)
N(N + 1) i ni
H =
∑i Ti
1 -
N(N - 1)
where:
t: Number of ex-aequo in each group and T: ( t - 1 ) t ( t + 1 ).
Example of Kruskall-Wallis Test In this example, we have two columns of data. One column
contains three treatments A, B and C. The other column contains
three sets of data for these three formulations (for example,
Tmax).
To complete a Kruskall-Wallis analysis with Kinetica:
2. Select the Unbalanced Block.kdb file, found in the Program


the program:

Figure 12-15. Kinetica Study Pane
4. Select Kruskall-Wallis from the Statistics menu. The

Kruskall-Wallis dialog appears.
Figure 12-16. Kruskall Wallis Dialog
5. Select “treatment” from the Group column list and “data”

from the Data column list.
Figure 12-17. Kruskall Wallis Dialog - Populated

You can view the results of the Descriptive Statistics in the Study

Friedman Test The Friedman rank sum test is the non-parametric equivalent of
ANOVA. It is appropriate for data arising from an unreplicated
complete block design, i.e., one in which exactly one observation
was collected from each experimental unit, or block, under each
treatment. The elements of y are assumed to consist of a group’s
effect, plus a blocks effect, plus independent and identically
distributed residual errors. The interaction between groups and
blocks is assumed to be zero.
In the context of a two-way layout with factors groups and

blocks, a typical null hypothesis is that the true location
parameter for y, net of the blocks effect, is the same in each of the
groups. The alternative hypothesis is that it is different in at least
one of the groups.
In the example file, Friedmantest, seven subjects underwent

treatment A, B, C, D, and E. The result for each treatment is
listed under the column y.
To run the Friedman test:
1. Click Statistics | Friedman…
Figure 12-18. Statistics Menu Options
2. Under the Friedman dialog box, select y for Data Column, t

for Treatment Column, and s for Subject Column. Click
OK.

Figure 12-19. Friedman Dialog
3. The result of the test is listed in the Study Info under the
Study pane.
Figure 12-20. Example – Test Results Displayed in the Study Pane
The ranks in each group j are summed. Let R(Xij) be the rank
assigned to Xij within treatment j. Average ranks are used in the
case of ties. Then the Friedman test is

H0: The treatment effects have identical effects
Ha: At least one treatment is different from at least one other

treatment
The test statistics used is:
12
χ2 =
nk(k + 1)
∑(R j − n(k + 1) / 2)2
If there are ties, then
k
n(k + 1) 2
(k − 1)∑ (R j − )
j=1 2
χ2 = n k
nk(k + 1) 2
∑
i=1
∑ (R( Xij ))2 −
j=1 4

Descriptive Statistics You can compute and display tables of descriptive statistics in
Kinetica using the Descriptive Statistics dialog.
Descriptive Statistics This dialog is accessed by selecting Descriptive Statistics from the
Dialog Statistics menu.
Presentation of Table for When a table is computed with Descriptive Statistics the results
Descriptive Statistics are written in the Info view of the Study pane. For this particular
test the organization of the table always appears as follows:
Column
x1
x2
x3
xn
N (sample size) 1
Mean (mean data value) 2
HarmoMean (harmonic mean data value) 3
GeoMean (geometric mean data value) 4
SEM (standard error of the mean) 5
SD (standard deviation) 6
Median (middle value found) 7
Min (minimum value found) 8

Column
Max (maximum value found) 9
Note The preceding example displays only one selected

column. ▲
The equations used to calculate the data in the Descriptive

Statistics Design for data1 table (i.e. 1, 2, 3) are listed in the
following table:
Point Equation Used
1 Count of the number of data values present
2 ∑x
N
3 1
Harmonic mean =
1
N× (∑ 1 x)
4 1
Geometric mean = (x 1 • x 2 • x 3 ...x N ) N
5 SD
SEM =
N
∑ x − ( ∑ x)
6 2
2
/N
SD =
N −1
7 If number of data values is an odd number:

n +1
median = th
2
Or
If number of data (N = 2k) is an even number:

+ (k + 1 ) th
th
k
median =
2

Point Equation Used
8 Search the data for the smallest value
9 Search the data for the largest value
Example of Descriptive In this example, we have two random data columns, data1 and
Statistics data2. The example given is the Descriptive Statistics on two
selected columns of data.
To generate descriptive statistics:
2. Select the DescriptiveStatistics.kdb file, found in the Program


the program:

Figure 12-21. Study Group Displayed in Study Pane
4. Select Descriptive Statistics from the Statistics menu. The

Descriptive Statistics dialog appears.
Figure 12-22. Descriptive Statistics Dialog
5. Highlight the “data1” and “data2” data columns.

You can view the results of the descriptive statistics on the two
data columns in the Study Info view of the Study pane.

The Paired and The hypothesis testing for the paired and unpaired t test generally
involves:
Unpaired t Test
1. Locating a sample statistic on an appropriate sampling
distribution.
2. Determining the relative distance of the statistic from the

mean of the distribution.
For two groups: “Data 1”and “Data 2,”
Data 1:
n1 = Number of data for group 1
m1 = Mean for group 1
Data 2:
n2 = Number of data for group 2
m2 =Mean for group 2.
The hypothesis of the test is that:
H0: m1 = m2
H1: m1 ≠ m2
and:
s2 = variance, where the variance is calculated by:
s 2
=
∑ ( x − m1) + ∑ ( x − m2)
2 2
n1 + n2 − 2
The value of t is calculated by:

m1 − m2
t=
s2 s2
+
n1 n2
The degree of freedom (df) is calculated as n1 + n2 -2.
The t (table) is calculated as t (df ; 0.05) with α = 0.05. The

conclusion is derived by the following rules:
• If t < t (table) then the difference is not significant.
• If t > t (table) then the difference is significant.
Note This test is only available if x (belonging to two groups)

follows a normal distribution. ▲
Power of the t Test The power of a test is the ability of a test to detect false null
hypotheses.
Kinetica calculates Z(1-beta) as:
m1 − m2
Z (alpha / 2) − Z (1 − beta ) =
2 ⎛1 1⎞
s ⎜⎝ n1 + n2 ⎟⎠
Z(alpha/2) = 1.96 with alpha = 0.05. (1-beta) is obtained from

Z(1-beta) by the normal Table. The power of the test is
represented by (1-beta).
To perform the paired and unpaired t test:
2. Browse through directories and files to locate and open the

appropriate .kdb file for the statistical analysis.

3. Select Student and Fisher Test from the Statistics menu. The
Student and Fisher Test dialog appears.
Figure 12-23. Student and Fisher Test Dialog
4. Select the Dataset Variable(s) or Dataset Column(s) radio

button.
5. Select the appropriate dataset variable or column from the

Data 1 list.
6. Select the appropriate dataset variable or column from the

Data 2 list.
7. Enter a value for α in the Significance field. By default, α is

set to 0.05.
8. Enter the name of the Reference formulation in the Ref field,

if required.
9. Select the Log Transformation for Data check box, if

required. Do not select this option if the data has already
been log-transformed.
10. Click Select Dataset. The Calculate Range dialog appears.

Figure 12-24. Calculate Range Dialog
11. Use your mouse and the CTRL key to select datasets
individually. Click Select All to include all datasets in the
analysis.
12. Click OK to exit the dialog and return to the Student and
Fisher Test dialog.
Grouping Datasets (optional) To group datasets:
1. Select the By Group check box and select the appropriate

group name from the available list.
2. Click OK to generate the report. You can view the results of

the Student t test in the Study Info view of the Study pane.

A. Population Methodology
The EM algorithm, initially proposed by Dempster, Laird and
Rubin (1977), is an iterative procedure developed for finding
maximum likelihood estimates for incomplete data. This is a two-
step algorithm represented by E-step and M-step. The E-step is
given current values of parameter estimates, to obtain the
expectation of individual parameters, conditional on the observed
data vector. The M-step is to obtain the ML posterior population
mean and variance together with the residual error variance, given
the individual parameter values. Further applications of this
algorithm in linear mixed effect models were performed by Laird
and Ware (1982), Strenio et al.(1983), and more recently by
Lindstrom and Bates (1988), with fewer assumptions on the
variance models and either maximum likelihood (ML) or
restricted maximum likelihood (REML) estimation.

Population Methodology
Models and Notation Let m denote the number of individuals j in the studied sample.
Let yj denote: the vector of nj measurements performed on
individual j given a specific design. Define βj as the (p x 1) vector
of parameters for this individual. We assume that for each
individual j, j=1 to m:
y j = f (x j ,β j ) + ε j (1)
where f is a known, possibly nonlinear, function of βj describing

the nj vector of responses, xj is the independent variable vector
for subject j, and εj is a residual error vector for subject j,
normally distributed with mean 0 and covariance matrix Rj. The
covariance Rj is assumed to be written:
R j = σ 2S j (β j ) (2)
where S j (β j ) is, for each individual, a known (nj x nj) matrix

depending possibly on the individual parameters, and σ 2 is an
unknown parameter to be estimated or is fixed to one if the error
is fully specified.
Covariate Models and The expression of βj in equation (1), called covariate model, can
Interindividual Variability be expressed as
β j = h(Z j , β j ) + η j (3)
where β is a (r x 1) vector of population parameters, and ηj

follows normal distribution with mean 0 and covariance matrix C
(p x p).
When the relationships between covariates and parameters are

linear, the expression (3) can be written:
β j = Z jβ + η j (4)
where Zj is a (p x r) matrix depending on the covariates Zj. When

no covariates are included, Zj = I and β is the (p x 1) vector of the
mean parameters.

The inter-individual variability, η j , in Kinetica Population is

assumed to follow either normal distribution or log normal
distribution,
• Normal distribution, η j ~ N(0, var)
• Log-normal distribution, exp(η j ) , where η j ~ N(0, var) .
In both cases it is assumed that ηj follows normal distribution

with mean 0 and covariance matrix C (p x p).
The EM Iterative Algorithm - Let β*j deNote: the individual parameters estimated from the
Two Stage Parameter Estimates
first stage,
β*j = Z jβ + η j + e*j (5)
Mj is the Variance Matrix of e*j . We use the following algorithm

after k steps,
Step E: Produce refined estimates of the β j :
(k + 1)
= (M −j 1 + (C ) −1 ) − 1(M −j 1β*j + (C(k)) − 1Z jβ (k))
(k)
β
j
Step M: Obtain updated estimates of the population parameters:
m (k ) (k + 1)
β(k + 1) = ∑ W β
j j
j
m
where, W j( k ) = ( ∑ Z 'j (C (k ) ) −1 Z j ) −1 Z 'j (C ( k ) ) −1
j
m m (k + 1) (k + 1)
C (k + 1) = m − 1 ∑ (M −j 1 + (C (k ) ) −1 ) − 1 + m − 1 ∑ (β − Z β (k + 1) )(β − Z β (k + 1) ) '
j j j j
j j
The iteration stops when the M-step converges; that is, until the
difference between successive estimates of β and C is sufficiently
small.

Population Parameter In this situation only a few measurements will have been collected
on each individual. It is not possible to estimate the parameters
Estimates - Sparse using standard procedures. Therefore, in this case, only the
Data Situation population approach can be used.
For equation (1), y j = f ( x j , β j ) + ε j , with β j = h ( Z j , β j ) + η j , the

problem is to estimate, from m vectors or measurements yj and
covariates Zj, the population parameters composed of the
components of β, the unknown parameters in C and in some
cases σ 2 . The iterative algorithm is composed of two steps; the E-
step and the M-step. From starting values of the population
parameters β(0), C(0), σ 2 (0) , the starting values βj(0) of the m
individual parameters are defined as follows:
βj(0) = h(zj,β(0) )
After k iterations, the algorithm proceeds as follows:
E-step – the individual parameters βj(k+1) are estimated by their

maximum a posteriori given the current population parameters
β(k), C(k), σ 2 (k) and assuming that the variance matrix of the
error is fixed and given by Rj(k) = σ2 (k) Sj(βj(k)).
M-step – the population parameters β(k+1), C(k+1), σ 2 (k+1)

are estimated by maximum likelihood given the current estimates
βj(k+1) of the individual parameters and using a first order
expansion of the model fj about βj(k+1), if f is not a linear model.
More specifically, it can be shown that these two steps can be

described by the following for linear covariate models.
During the E-step for each individual j, the individual parameters

βj(k+1) are estimated through minimization of the following
objective function by a standard least-squares algorithm, using
βj(k) as starting values:
Objj (β(jk +1) ) = ( y j − f (β(jk) ))' (R(jk) )−1 (y j − f (β(jk) )) + (β(jk) − Z jβ(k) )' (C(k) )−1(β(jk) − Z jβ(k) )
During the M-step, first β(k+1) is estimated from Zj and βj(k+1)

by linear regression; the estimate is the value minimizing the sum
over the m individuals:

m ⎛ (k + 1) '
∑ ⎜β j − Z jβ(k ) ⎞⎟ ⎛⎜ β (k + 1) − Z jβ(k ) ⎞⎟
j⎝ ⎠⎝ j ⎠
Then the unknown terms in C are estimated by:
( ) m ( ) ( ) ( )'
C k + 1 = m − 1( ∑ C jk + η jk + 1 η jk + 1 )
j =1
where ηj(k+1) are the estimates of individual random effects,

given by:
( ) ( ) ( )
η k + 1 = β k + 1 − Z jβ k + 1
j j
Cj(k) are the conditional variances of βj(k+1) which correspond

to the estimation variances of βj(k+1), usually obtained during
the first step, and given by:
(k ) −1
C (jk ) = G j (β(jk +1) )(R (jk ) ) −1 G 'j (β(jk +1) ) + (C )
Last, if σ 2 is not known, it is estimated by after k steps:
1 m (k) (k) (k )
σ 2( k +1) = ( ∑ ((e j )'e j + σ 2( k ) tr (I − σ 2( k ) (V j ) −1 )
n j
where, e (jk ) = YObs , j − f ( x j , β(jk ) ) , and Vj(k ) = σ 2j( k ) I j + G j C(jk ) G 'j
tr(A) denotes the trace of the matrix A (sum of the diagonal

elements). Gj is the Jacobian matrix with parameter βj.

Individual Parameter The Bayesian methodology allows the pharmacokinetic

Estimates: Bayesian Fit parameters for an individual to be estimated, when there is a prior
knowledge of the mean and dispersion of the pharmacokinetic
parameters in the population to which the selected individual
belongs.
Kinetica Population uses a Maximum A-Posteriory Probability

(MAP) Bayesian fitting procedure to combine the prior
knowledge (the population parameter values) and the individual
available information (such as drug sample(s), individual
demographic and/or concomitant measurement, usually referred
to as covariables) in order to estimate the individual parameters.
The MAP Bayesian procedure estimates the individual parameters

minimizing the criteria:
nj (Yobsi − f (βˆ k , t i )) 2 p (β kj − βˆ k ) 2
∑ + ∑
i =1 σi2 k =1 σ 2k
where
Yobsi are the observed concentrations for the individual,
f ( β k , t i ) are the predicted concentrations estimated using the

population information,
σ i2 are the measurement error variances,
βˆk are the population parameter values,
β k are the parameter values (to be estimated) for individual j,
σ 2k are the population parameter variances,
k indicates different parameters for subject j,
nj is the number of samples for subject j.
Note This MAP Bayesian fitting procedure can operate with

only a single observation (changed here) (Yobsi ) , even though
many parameter values are to be fitted. ▲

Maximum Likelihood The EM algorithm computes the maximum likelihood parameter

Evaluation and estimate without explicitly evaluating the likelihood function.
Comparison of Models
In order to compare two hierarchically related models using a
likelihood ratio test, the likelihood function is evaluated at the
end of the algorithm.
The value of this function can be approximated using a

linearization of the model around the individual parameter
estimates.
The Logarithm of Likelihood function (LL) can be written as:
1
LL = (L − ln(2π)∑ n j )
2
where:
L = − ∑ j ln det Vj + ( y j − f j (β j ) − G j (β j )(h (z j, β) − β j ))' Vj− 1( y j − f j (β j ) − G j (β j )(h (z j, β) − β j ))
V j = G j ( β j )CG j ( β j )' + R j
∑n j is the population sample size
Model Evaluation Suppose that β j , a model of B with n p parameters, is a sub-model

of A, a model with n p + q parameters, then the difference
LL A − LL B can be approximated by a χ 2 distribution with q
degrees of freedom. Therefore this test can be used to compare
two nested models A and B.
Using the likelihood value, one can also compute two criteria:
(− LL + n p )
Akaike criterion: AIC =
∑n j
Schwartz criterion:

(− LL + n p / 2ln(∑ nj ))
BIC =
∑ nj
where n p is the total number of parameters to be estimated and
∑ nj is the population sample size. Therefore, to compare two
models one can choose, according to the principle of parisimony,
the model with the smallest criteria.
The following outputs also provide the information for model

evaluation:
The estimation of the expected concentration for each individual

in a population, which is not necessarily included in the original
analysis.
The estimation of the expected individual parameters given the

populations estimated values (using a MAP procedure).
The computation of the appropriate statistical tests to evaluate

the distribution properties of the differences between the expected
and the observed data.
For each concentration, a Standardized Concentration Prediction

Error (SCPE) is calculated as follows:
Yobsij − f (β j , t ij )
SCPE ij =
Sd
Where j refers to the subject, i to the time of the sample.
Yobs ij is the observed concentration
f (β j , t ij ) is the MAP predicted concentration
β j is the individual parameter posterior estimate computed using

the appropriate covariable dependency
Sd is the predicted standard deviation defined as the diagonal of

the variance matrix Vj:

Vj = G j (β j ) * C * G j (β j )'+ R j
where:
G j (β j ) is the Jacobian matrix with β j parameter
Rj is the residual error matrix
For each parameter a value is estimated and the normalized SPPE

(Standardized Parameter Prediction Error) values are computed
as:
β kj − β k
SPPEkj =
σ (βk )
k = parameter
j= subject
βk= mean population value for parameter k
σ(βk)= population standard deviation
Under the assumption of a correct regression model and unbiased

parameter estimates, the SPPEij values should have a mean value
of zero and a variance equal to one.

Initial Parameter Initial parameter estimates are required as a starting point for EM
algorithm. Kinetica Population has two tools for estimating some
Estimates initial values, one is the Initial Estimate Assistant, and the other is
the Simplex method.
Initial Parameter Initialization Assistant applies the stripping method to naïve

Estimation Assistant average data (NAD), or naïve pooled data (NPD), or individual
data (standard two stage method) to obtain the parameter values.
These values are then used as initial estimates for the EM
algorithm. These methods are sometime used to analyze
population data, however, in Kinetica Population, they are only
used as a tool for initial parameter estimation.
Naive Pooled Data Combine all the data as if they came from a single individual (a
(NPD) “reference” individual).
Fit all data from this “reference” individual using classical fitting
procedures.
2
OBJ(φ ) = Σ⎛⎜ Y −Y ⎞ Wi
⎟
⎝ obsi predi ⎠
Naive Averaged Data (NAD) Obtain the average concentration across individuals at each time
point.
Fit model to the averaged concentrations (e.g., weighted least

squares) and the parameters that would represent the parameters
from a “mean” individual.

2
⎛
OBJ(φ ) = Σ⎜ Y −Y ⎞ Wi
⎝ avgobsi predi ⎟⎠
Standard Two Stage (STS)
Step 1: Estimate an individual subject’s PK and/or PD parameters

from rich data using standard fitting procedures.
2
OBJ(φ ) = Σ⎛⎜ Y −Y ⎞ Wij
⎝ obsij predij ⎟⎠
Step 2: Estimate the population parameters across the subjects

(mean, variance, covariance).
Arithmetic Mean and Variance The equations for arithmetic mean, µ, and variance, Ω, are given
below:
Σφ
j
µ=
N
2
Σ⎛⎜ φ − µ ⎞⎟
j
Ω= ⎝ ⎠
N
Simplex Method The simplex method finds the minimum of an unconstrained

multivariable, nonlinear function by minimizing the objective
function:
∑ ( y i − f ( x, p)) 2
where yi represents the observed measurements, f is the structural

model and p, the unknown parameters.
The procedure is an extension of the simplex method by

Spendley, Hext, and Himsworth ("Sequential Applications of
Simplex Designs in Optimization and Evolutionary Operation",

Technometrics, 4, 441-461, 1962). Both methods utilize a

regular geometric figure (called a simplex) consisting of N+1
vertices. This method accelerates the simplex method and makes
it more general. The procedure is based on the work by J. A.
Nelder and R. Mead (“A Simplex Method for Function
Minimization,” Computer J., 7, 3080313, 1964). This simplex
method adapts itself to the local landscape, using reflected,
expanded, and contracted points to locate the minimum.
Unimodality is assumed and thus several sets of starting points
should be considered. Derivatives are not required.
The algorithm proceeds as follows:
1. A starting point, P1, is selected.
2. A starting “simplex” is constructed consisting of the starting

point and the following additional points:
Pj = P1 + Sj, with j = 2, 3, . . . ., N +1
where Sj is determined from the following table
j S1, j S2, j ... S N −1, j SN , j
2 p q ... q q
3 q p ... q q
. . . . .
. . . . .
. . . . .
N q q ... p q
N+1 q q ... q p
where N is the total number of variables
a = side length of simplex

a
p= ( N + 1 + N − 1)
N 2
a
q= ( N + 1 − 1)
N 2
Once the simplex is formed, the objective function is

evaluated at each point. The worst point (highest value of
objective function) is replaced by a new point. Three
operations are used: reflection, contraction, and expansion. A
reflected point is located first as follows:
Pi , j (reflected) = Pi , c + α ( Pi , c − Pi , j ( worst ))
where i = 1,2 . . ., N and α is a positive constant (in Kinetica

Population the α value is set to 1.0). Pi ,c are the centroid
coordinates of all points excluding the worst point and are
calculated from the following:
1 K
Pi , c = [∑ pi , j − pi , j ( worst )], i=1,2, . . ., N
k − 1 j =1
where K = N+1.
3. If the reflected point has the worst objective function value of

the current points, a contracted point is located as follows:
Pi , j (contracted) = Pi , c − β ( Pi , c − Pi , j ( worst )),
where i = 1, 2, . . . , N and β lies between 0 and 1 (in Kinetica

Population β is set to 0.5).
If the reflected point is better than the worst point but is not
the best point, a contracted point is calculated from the
reflected point as follows:
Pi , j (contracted) = Pi , c − β ( Pi , c − Pi , j (reflected )),
where i = 1, 2, . . . , N.

The objective function is now evaluated at the contracted

point. If an improvement over the current points is achieved,
the process is restarted. If an improvement is not achieved,
the points are moved one half the distance toward the best
point;
Pi , j (new) = ( Pi , j (best ) + Pi , j (old )) / 2
where i = 1, 2, . . ., N.
The process is then restarted.
4. If the reflected point (calculated in step 3) is the best point,

an expansion point is calculated as follows:
Pi , j (expansion) = Pi , c + γ ( Pi , j (reflected ) − Pi , c )
where i = 1, 2, . . ., N and γ is a positive constant (in Kinetica

Population γ is set to 2.0). If the expansion point is an
improvement over the reflected point, the reflected point is
replaced by the expansion point and the process restarted. If
the expansion point is not an improvement over the reflected
point, the reflected point is retained and the process restarted.
5. The procedure is terminated when the convergence criterion

is satisfied or a specified number of iterations has been
exceeded.
The convergence criteria is defined as follows:
The program will terminate if EJ<0.01, where:
N 1
EJ = (((∑ ( Z i − Pi , c ) 2 − ( Z worst − Pi , c ) 2 ) / N ) 2
i =1

Minimization At each iteration of the algorithm, the estimation of the

individual parameters of step E is performed using a Gauss-
Algorithm Marquardt algorithm [Marquardt, D.W., 'An algorithm for
least-squares estimation of nonlinear parameters', Journal of the
society for Industrial and Applied Mathematics, 11, 431-441
(1963)], with a relative parameter accuracy set by default at 1%.
Marquardt’s method represents a compromise between the

linearization method and the steepest descent method and
appears to combine the best features of both while avoiding their
most serious limitations.
The principle of Marquardt’s method can be explained briefly as

follows:
Suppose we start from a certain point in the parameter space, β.

If the method of steepest descent is applied, a certain vector
direction, δg where g stands for gradient, is obtained from
movement away from the initial point. Due to attenuation in the
S(β) (S is the objective function to be minimized in β) contours
this may be the best local direction in which to move to attain
values of S(β) but may not be the best overall direction.
However, the best direction must be within 90° of δg or else

S(β) will be larger locally. The linearization method leads to
another correction vector δ t given by solving
Aδ t = g
where
A = P′P

⎛ ∂f ⎞
P= ⎜ i ⎟
⎜ ∂β ⎟
⎝ j⎠
n
∂f i
g= ∑( y
i =1
i − fi )
∂β j
Marquardt found that for a number of practical problems to be

studied, the angle between δg and δt fell in the range 80° - 90°.
In other words, the two directions were almost at a right angle.
The Marquardt algorithm provides a method for interpolating
between the vector δg and δt and for obtaining a suitable step
size as well.

Termination Criteria A general termination strategy for the two-step algorithm is

defined as follows. The algorithm terminates after the M-step
of EM Algorithm when the relative change between two iterations for each of the
estimated population parameters is lower than 1%. Then another
E-step is performed to estimate the individual parameters.

Differential Equation Kinetica Population utilizes a numerical integration algorithm

based on a Runge-Kutta-Fehlberg method [Forsythe G.E.,
Solver Malcolm M.A. and Moler C.B., Computer Methods for
Mathematical Computations, N.J., Prentice Hall Inc. 1977] to
compute the regression function values, when the structural
model is described by a system of differential equations. This is a
5th order method with variable step-size control. Initially a step
length satisfying a local error criterion is estimated, then the 4th
and 5th order Runge-Kutta approximation of the solution are
computed and used to estimate the local error. The 5th order
estimation is used as the solution if, and only if, the estimated
error is less than a fixed tolerance level. If this is not the case, the
step size is reduced until the error criterion is satisfied.

Stepwise Method Stepwise regression is a useful tool for screening covariates

automatically. There are forward selection and backward
elimination methods. Each method adds and/or deletes covariates
sequentially and systematically on the basis of F-test. In the case
of Forward Selection, the initial model contains only a constant
term. The procedure selects for entry the covariate that produces
the largest R2 of any single covariate. The second covariate is
chosen if it produces the largest increase in R2 in the presence of
the previous covariate, or the largest partial F. This process is
continued until no more variates are admitted to the equation.
The forward selection of stepwise algorithm is described below:
Step 1 Introduce one covariate, called Cov1, to equation, P = θ1
P = θ + θ Cov1 (2)
1 2
and calculate FK,T-K-1 =(SSreg/K)/ s2
Then use p-value to check if F is significant with the entry of

Cov1.
Step 2 If F is significant with the entry of Cov1, the second covariate,

called Cov2, is added to equation (2)
P = θ + θ Cov1 + θ Cov2 (3)

1 2 3
RSS(Cov1,1) - RSS(Cov1, Cov2,1) RSS(Cov1, Cov2,1)

Fchange = /
(K − P) T -K -1
Then use p-value to check if Fchange is significant with the entry

of Cov2.
Step 3 Repeat Step 2 until there are no more covariates to be admitted to

the equation.

In Step 1 to Step 3, Rss = ∑ ( Yobs − Ycalc ) 2 ,
SSreg = ∑ ( Ycalc − Ymean) 2 ,
s2=Rss/(T-K-1)
where K is the number of covariates used in the new equation,

and P is the number of covariates in the previous step.

Population Hard- The equations for population methods are identical to those
described for other Kinetica hard-coded methods. For more
Coded Equations information, see the section, “Available Models” in the chapter,
“Performing Compartmental Analysis.”
Exceptions For the following six methods, where Clearance, CL, is used as a
parameter rather than Kel (CL = V*Kel), the expressions of the
equations can be obtained by replacing Kel
CL
with .
V
• PopFitBolusInput1comp (single dose intravenous micro

constants using 1 compartment model)
• PopFitBolusInput2comp (single dose intravenous micro

constants using 2 compartment model
• PopFitFirst0orderinput1comp(single dose zero order micro

• PopFitFirst0orderinput2comp (single dose zero order micro

constants using 2 compartment model)
• PopFitZeroOrderinput1comp (single dose zero order micro

• PopFitZeroOrderinput2comp (single dose zero order micro

For more information related to these six models, see the chapter,
“Performing Compartmental Analysis.”

References Amisaki, T. and Tatuhara, T. 'An alternative two stage method

via the EM-algorithm for the estimation of population
pharmacokinetics parameters', Journal of Pharmacobio-Dynamics,
11, 335-348 (1988).
Beal, S.L., NONMEM Users Guide VII: Conditional estimation

Methods. NONMEM Project Group, University of California -
San Francisco (1992).
Beal, S.L. and Sheiner, L.B., 'The NONMEM system', The

American Statistician, 34,118-119 (1980).
Davidian, M. and Giltinan, D.M. 'Some general estimation

methods for nonlinear mixed-effects models', Journal of
Biopharmaceutical Statistics, 3, 23-55 (1993).
Dempster, A.P., Laird, N.M. and Rubin, D.B. 'Maximum

likelihood from incomplete data via the EM algorithm', Journal
of the Royal Statistical Society, Series B, 39, 1-38 (1977).
Laird, N.M. and Ware, J.H. 'Random-effects models for

longitudinal data', Biometrics , 38, 963- 974 (1982).
Lindstrom, M.J. and Bates, D.M. 'Newton-Raphson and EM

algorithms for linear mixed-effect models for repeated-measures
data', Journal of the American Statistical Association, 83, 1014-
1022 (1988).
Lindstrom, M.J. and Bates, D.M. 'Nonlinear mixed effects

models for repeated measures data', Biometrics, 46, 673-687
(1990).
Racine-Poon, A., 'A Bayesian approach to nonlinear random

effects models', Biometrics, 41, 1015-1023 (1985).
Racine-Poon, A. and Smith, A.F., 'Population models' in Berry,

D.A. (Ed.) Statistical Methodology in the pharmaceutical sciences.
Marcel Dekker, New York, 1990, pp.139-162.
Sanathanan, L.P. 'Random effects modeling in population

kinetic/dynamic analysis', Drug Information Journal, 25, 307-318
(1991).

Sheiner, L.B., Rosenberg, B. and Marathe, V.V., 'Estimation of

population characteristics of pharmacokinetics parameters from
routine clinical data', Journal of Pharmacokinetics and
Biopharmaceutics, 5, 445-479 (1977).
Steimer, J.L., Mallet, A., Golmard, J.L. and Boisvieux, J.F.,

'Alternative approaches to estimation of population
pharmacokinetic parameters; comparison with the nonlinear
mixed effect model', Drug Metabolism Reviews, 15, 265-292
(1984).
Steimer, J.L., Mallet, A. and Mentré, F. 'Estimating inter-

individual pharmacokinetic variability', in Rowland, M.,
Sheiner, L.B. and Steimer, J.L. (Eds.) Variability in Drug
Therapy: Description, Estimation and Control., Raven Press, New
York, 1985, pp. 65-111.
Strenio, J.F., Weisberg, H.I. and Bryck, A.S., 'Empirical Bayes

estimation of individual growth-curve parameters and their
relationship to covariates', Biometrics, 39, 71-86 (1983).
Vonesh, E.F. and Carter, R.L. 'Mixed-effects nonlinear regression

for unbalanced repeated measures', Biometrics, 48, 1-17 (1992).

Notes

B. Kinetica Population Method
Writing
You can write soft-coded population methods using the Macro
Editor located in the Study pane of Kinetica. When you are
finished writing the population method, click the Start Running
the Script button on the toolbar to run/insert the method.
The method is added to the list of population methods displayed
in the Method Selection dialog.
Following are three examples that will help you to write a

population method:
• OSMacro2compBasic – shows you a soft-coded population

method similar to the file PopFitFirstOrderInput1comp.
• Multiple Dose Example – provides an example of how to

create a multiple dosing regimen of an IV Bolus using macro
constants.
• IV RungeKuttaMultidose – gives an example of how to create

a multiple dosing regimen of a 1 compartment IV Bolus
using micro constants.

Kinetica Population Method Writing
OSMacro2compBasic The OSMacro2compBasic method is a basic population method.
'Basic Population Method

sub FirstPopMethod()
'Indicate the fitting method name

PopMethod.Name = " OSMacro2compBasic"
'Method description (will be used as tool tip in the method selection dialog)
PopMethod.AddDescription("My Soft Coded ")
PopMethod.AddDescription("Population Method Description")
'Set the algorithm to be called, and set the subroutine name to be called
'where all models are ‘defined for all datasets
PopMethod.GeneralAlgoOptions("EM","procmodels")
'Add a parameter or a constant to be used by one of the models

PopMethod.AddInOutVar("D")
PopMethod.AddInOutVar("Ka")
PopMethod.AddInOutVar("Vd")
PopMethod.AddInOutVar("Cl")
'Here, Model is the dataset variable number which contains the index of the
'model linked to a dataset
PopMethod.AddDatasetModelNumVar("Model")
'Indicate that D is linked to the model which index value is 1
PopMethod.LinkVarToModel("D",1)
'Indicate that D is linked to the model which index value is 2
PopMethod. LinkVarToModel ("D",2)
'Indicate that Ka is linked to the model which index value is 1, Ka is only

'linked to the model which index value is 1
PopMethod. LinkVarToModel ("Ka",1)
'Indicate that Vd is linked to the model which index value is 1

PopMethod. LinkVarToModel ("Vd",1)
'Indicate that Vd is linked to the model which index value is 2

PopMethod. LinkVarToModel ("Vd",2)
'Indicate that Cl is linked to the model which index value is 1

PopMethod. LinkVarToModel ("Cl",1)
'Indicate that Cl is linked to the model which index value is 2

PopMethod. LinkVarToModel ("Cl",2)
'Call the dialog to add this method to the current study

PopMethod.AddPopMethodToStudy
End sub

sub procmodels(nb as integer, Model as integer, dtname as string)
'Input of procmodels:
'nb is the number of time for the current dataset named dtname.
'Model is the index indicating which model has to be selected for this
'dataset.
'example: model index 1: os

if Model = 1 then
'Parameters are taken in the order defined by AddInOutVar

D = PopParam(1)
Ka = PopParam(2)
Vd = PopParam(3)
Cl = PopParam(4)
Kel = Cl/Vd
'PopYCalc is an internal array of double for Kinetica to get the result

'PopIndepVal is an internal array of double which contains all the independent
'values column for the current dataset (named dtname)
for i = 1 to nb
PopYCalc(i) = D / Vd * (Ka / (Ka - Kel) ) * (exp( -Kel * PopIndepVal (i)) - exp(-Ka *
PopIndepVal (i) ))
next i
end if
'example: model index 2: os

if Model = 2 then
'Parameters are taken in the order they are defined by AddInOutVar, but Ka
'doesn't belong to this model so, here is the new order
D = PopParam(1)
Vd = PopParam(2)
Cl = PopParam(3)
Kel = Cl/Vd
for i = 1 to Note:
PopYCalc(i) = D / Vd * exp( -Kel * PopIndepVal (i))
next i
end if
'If you want to make a multiple dose fitting, you have to use a line of code
'such as: Dosei = GetValue (dtname, "AdminWorksheet", "DoseColumn", ‘LineNumber , pStatus)
where pStatus is a Long which indicates if the dose is
'missing or not ‘(3 = missing,0 = 'normal), AdminWorksheet (dim 'AdminWorksheet as string) is
the worksheet where the admin 'column is,
'DoseColumn is the dose column name (dim DoseColumn as string), LineNumber is
'a long, Dosei ‘is the return ‘value (a 'double).
'With this line of code you can get all the doses.
'You can also use GetNbValue (dtname, "AdminWorksheet", "DoseColumn") to get the number
'of 'value in the column DoseColumn for the dataset dtname. The return value is 'a long.
End sub

Multiple Dose The sample code below is an example of how to create a multiple
dosing regimen using macro constants.
Example
'This code is a multiple dose sample for population fitting
sub MultidoseSample()
'Method name
PopMethod.Name = "MultidoseSample"
'Method description
PopMethod.AddDescription("Multidose ")
'Method description
PopMethod.AddDescription("Population fitting")
'General options, "procmodel" is the model subroutine to be called

PopMethod.GeneralAlgoOptions("EM","procmodel")
'Add a variable to be used for the current model

PopMethod.AddInOutVar("V")
'Add a variable to be used for the current model

PopMethod.AddInOutVar("Cl")
' Note: when there is only one model you do not have to link
' your variable to an index model.
'Add the model to the study

End sub
' Subroutine to be called to compute the model

sub procmodel(nb as integer, Model as integer, dtname as string)
' "nb" is the number of elements in the internal array PopIndepVal.

' "PopIndepVal" is a internal column of double which contains
' the abscisse of the observed value.
' Here "Model" is only needed if you fit with multiple model (which is not the
' case here).
' "dtname" is the name of the dataset we are going to compute
' PopYCalc (PopYCalc is also an internal array for the EM algorithm to receive the
'computed values).
'variable declaration
dim diff as double
dim LineNumber as long
dim pStatus as long
dim nAdmin as integer
dim dose as double
dim j as integer
dim admintime as double

dim newdtname as string
' get the parameter in the same order as they are defined.
V = PopParam(1)
Cl = PopParam(2)
newdtname = dtname
'Those lines are added in order to plot a population graph.
'When Kinetica wants to plot the population graph,
'it will call this model with "#No dataset" instead of
' a dataset name. Then we have to choose which multiple dose
'column to select. Here we choose, for example, the column dose of dataset 51.
' Note: In our case all the datasets have the same dose column. Then we can
'draw a graph.
if dtname = "#NoDataset" then
newdtname = "51"
end if
' Get the number of values in the column Dose, in the worksheet MultiAdmin,
' for the dataset newdtname
nAdmin = GetNbValue(newdtname, "MultiAdmin","Dose")
for j = 0 to nAdmin - 1
'Get the value and the status in the column Dose, in the worksheet MultiAdmin at the
'index j for the dataset newdtname
dose = GetValue(newdtname, "MultiAdmin","Dose", j, pStatus)
'status conventions are:
'pStatus = 0 for normal; 1 for indetectable; 2 for outlier; 3 for missing; 4 for error.
' Here we check the status
if pStatus = 0 then
' Get the value and the status in the column Dose, in the worksheet MultiAdmin at the
'index j for the dataset newdtname
admintime = GetValue(newdtname, "MultiAdmin","Time", j, pStatus)
' Now compute PopYCalc
for i = 1 to nb
diff = ( PopIndepVal(i) - admintime )
if diff >= 0 then
PopYCalc(i) = PopYCalc(i) + dose/V*exp(-Cl/V*diff)
end if
next i
end if
next j
End sub

IV The sample code below creates a multiple dosing regimen of a 1

compartment IV Bolus using micro constants.
RungeKuttaMultidose
'Global Variables declaration
'Variable for differential system
dim Z1 as Double
dim DZ1 as Double
dim LineNumbe as long
dim curNextTimeIndex as long
' Dose administration status
dim pStatu as long
' number of administrations for this dataset

dim nAdmin as integer
' time of the dose administration

dim admintime as double
dim diff as double
dim Dose as double
dim maxTime as double
dim NextAdmintime as double
dim i as Integer
dim ret as Integer
dim hmod as long
sub Fit_Interactive_model ()
PopMethod.AddInOutVar("V")
PopMethod.AddInOutVar("k10")
PopMethod.GeneralAlgoOptions("EM","procmodel")
' Function to be called at the begining of the fitting
' in order to declare the differential system equation
PopMethod.BeginFunctionToCall("InitDifferentialEquation")
' Add the method to the study

End sub
dim V as double
dim k10 as double
sub InitDifferentialEquation()
hmod = NewInteg("Deriv")
ret = DeclareComp(hmod, Z1, DZ1)
End sub
'Function to be called to compute YCalc

sub procmodel(nb as integer, Model as integer, dtname as string)

'Get parameters value

V = PopParam(1)
k10 = PopParam(2)
Z1 = 0
' Get the number of the value in the column Dose in the worksheet
' MultiAdmin for the dataset dtname
nAdmin = GetNbValue(dtname, "MultiAdmin","Dose")
'for each dose administration time

for LineNumber = 0 to nAdmin - 1
' Get the value and the status in the Dose column
' at the index LineNumber for the current dataset
Dose = GetValue(dtname, "MultiAdmin","Dose", LineNumber , pStatus)
' status conventions are:

' pStatus = 0 for normal; 1 for undetectable; 2 for outlier;
' 3 for missing; 4 for error.
' Here we check the status
if pStatus = 0 then
' Get the value and the status in the Dose column
' at the index LineNumber for the current dataset
admintime = GetValue(dtname, "MultiAdmin","Time", LineNumber , pStatus)
curNextTimeIndex = LineNumber
maxTime = PopIndepVal(nb) + 1
NextAdmintime = maxTime
do
if curNextTimeIndex > nAdmin - 2 then
exit do
end if
NextDose = GetValue(dtname, "MultiAdmin","Dose", curNextTimeIndex+1 , pStatus)
if pStatus = 0 then
NextAdmintime = GetValue(dtname, "MultiAdmin","Time", curNextTimeIndex+1 , pStatus)
exit do
else
NextAdmintime = maxTime
end if
curNextTimeIndex = curNextTimeIndex + 1
loop
' initial time for Runge Kutta integration

SetIntegCurrentTime hmod, admintime
Z1 = Z1 + Dose/V
For i=1 To nb
' For each independant value
diff = ( PopIndepVal(i) - admintime )
'if current time is after the current admin time, then
if diff >= 0 and NextAdmintime > PopIndepVal(i) then
' Compute new comp values
ret = IntegTo(hmod, PopIndepVal(i))
PopYCalc(i) = Z1
' Get corresponding computed value

End If
Next i
End If
Next LineNumber
End Sub
Sub Deriv (Byval t as double)

DZ1 = -Z1*k10
End Sub

Index
Step 5, 188
Column Units, 80
A
Computational Algorithm
Absorption, 4, 457, 497, 515, 518 Differential Equation Solver, 736
Initial Parameter Estimates
Add Free Comment, 193, 235 Method, 729
Minimization Algorithm, 733
Adjusting Columns & Rows, 55 Stepwise Regression, 737
Termination Criteria, 735
All Properties, 218, 235
Concentration method, 636
All Variables, 45
Configuring Units, 73
ANOVA, 659
Convolution/Deconvolution, 4
Applying Axis Scale, 194
Correlation Matrix
Applying Graph Templates, 232 Fitting, 447
Automatic Graphs, 212 Creating Mean Curves By Group With Statistics, 207
Available Views, 143 Creating Standard or Overlay Mean Curves With

Statistics, 205
Customizing the Normal Kinetica Template, 66

B
Batch Graphs, 243
D
Bayesian fit, 636
Data Column, 115, 116, 140, 154, 160
Data Columns, 212, 213

C Data Format, 130
Cells Dialog Box, 52
Data Layout, 100, 108, 129
Changing Fitting, 546
Data Preview, 143
Changing Your Dataset View, 58
Data View, 131
Chart Wizard
Dataset Graph, 47
Starting, 177
Step 1, 177 Dataset Graph Options, 192
Step 2, 183
Step 3, 184 Dataset Group, 16, 19, 191, 210, 230
Step 4, 185

Index
Dataset Pane, 30, 46 Extravascular, 157, 220, 223, 226, 230, 336, 360, 361,
369, 412, 420, 422, 423, 427, 429, 431, 434, 437, 449, 456,
Default Data Structure, 61 458, 470, 481, 482, 507, 514, 517, 520, 527, 537
Delete Commands, 26 Extravascular Fitted Model

Equations for PK Parameters, 437
Deleting a Column, 30
Deleting a Dataset Numerical Field, 33

F
Deleting a Study Numeric Field, 31
First Order Absorption, 515
Deleting a Study Text Field, 32
FitMacroExtravascular, 422, 429, 457, 517
Deleting a Worksheet, 29
FitMacroIVInf, 422, 429, 465, 546
Deleting Methods, 33
FitMicro0orderInput, 468
Differential Equation Solver, 736
Fitting, 444 FitMicroIV, 475
FitMultiMicro, 430, 497
E FitMultiMicroExtravascular, 427, 429, 483
Edit Menu FitMultiMicroIVBolus, 427, 429, 485, 488, 493, 500,

511
Move Columns, 56
EM Iterative Algorithm FitMultiMicroIVInf, 427, 430, 491
Two Stage Parameter Estimates, 721
Fitting, 4, 426
Emax, 503, 504, 505, 506, 507, 509, 511, 512, 519, 527,
Correlation Matrix, 447
529, 531, 532, 537, 541, 547
Differential Equation Solver, 444
Goodness of Fit, 445
Enzyme Kinetmatics, 4
Initial Parameter Estimates, 440
Macro or Micro Constants, 421
Error, 114, 115, 140, 154, 160, 206, 214
Marquardt's Principle, 443
Method of Administration
Exchange Pane, 50
Bolus, 424
Extravascular, 424
Exporting Data, 168, 170
IV Infusion, 425
Micro and Macro Constants, 426
Exporting Data To External Databases, 168
Multiple Dose, 424
Exporting data to Microsoft Word, 654
PD Analysis, 502
Residuals, 448
Exporting Graphs, 243
Single Dose Zero Order Input Macro Constants
Template, 451
Exporting Results to Microsoft Word and Excel, 170
Statistics & Goodness of Fit, 445
Stripping, 441
Extract Study Command, 38
Stripping, Failure of, 441
Weighted Residuals, 448
Extracting Fields from A Study, 39
Weighting Schemes, 442

Index
Formatting Cells, 53 Importing Data from Watson LIMS, 162
Formatting Kinetica Spreadsheets, 52 Importing Data in Proprietary Formats, 156
Friedman Test, 707 Importing Miscellaneous Data, 165
Importing PCNonlin Files, 167
G Importing SIPHAR Files, 166
Gallery Interface, 233 Importing XPD Files, 165
Gallery Pane, 49 Individual Parameter Estimates

Bayesian Fit, 724
Gauss-Marquardt Algorithm, 733
Initial Parameter Estimates
Generating a parameter distribution plot, 250 Fitting, 440
Method, 729
Getting Units, 85
Insert Commands, 17
Goodness of Fit, 445
Inserting and using the Get Column Unit Method, 85
Graph Buttons, 212
Inserting and Using the MakeRateUnit Method, 82
Graph Gallery, 176, 204, 206, 216, 230, 233, 236, 238,
535 Inserting and Using the Set Column Unit Method, 80
Graph Methods, 214 Inserting and Using the XY Unit Method, 87
Graph Properties, 194, 211 IV Bolus, 336, 337, 340, 369, 420, 422, 424, 427, 428,
429, 430, 432, 435, 449, 450, 460, 474, 485, 487, 499, 507,
514, 515, 529, 532
IV Infusion, 336, 350, 353, 354, 369, 404, 420, 421, 422,
H 427, 429, 430, 431, 433, 436, 449, 450, 464, 477, 478, 490,
492, 507, 514, 515, 539, 542, 546
Hard-Coded Methods, 258
Hill, 505, 506, 507, 512, 519, 527, 531, 537, 541, 547
Hot Graph, 191, 201 K
Hysterisis Graph, 524 KDB, 64, 237, 239, 240, 241, 572, 573
KDB File, 240
KGG File, 236, 238, 239, 240

I
Kinetica Basic, 258
Importing Data from ASCII Files, 128
Kinetica Insert Commands, 17
Importing Data from Databases, 142
Kinetica Main Menu, 16
Importing Data from Excel Files, 107

Index
Kinetica Study Pane, 45 Individual Parameter Estimates

Bayesian Fit, 724
Kinetica Toolbar, 41 Methodological Background, 719
Model Validation, 726
Kinetica Views, 45 Models and Notation, 720
Population Parameter Estimates
Kinetica Workspace, 14 Sparse Data, 722
References, 740
Methods, 6, 258
L Methods Group, 48
Latin Square, 673 Methods Menu
Latin Square with Greater Than Two Formulations LZ Graph, 198
Statistical Analysis, 680 Methods Pane, 48, 91, 93
LIMS, 104, 106 Micro and Macro Constants
Linear, 403, 502, 511, 527, 537, 547 Fitting, 426

Micro Constants, 421, 427, 429, 430, 432, 433, 449, 450,
Linear Model, 502, 520, 542 467, 470, 474, 477, 478, 481, 482, 485, 487, 490, 492, 496,
499
Log-Linear, 502, 511, 527, 537, 547
Microsoft Excel, 6, 366, 380, 511, 525, 536, 545
Microsoft Word, 6, 170, 171, 176, 204, 206, 244

M
Microsoft® Excel, 571, 572
Macro Editor, 45
MicroToMacro, 422, 427, 469, 472, 486, 491, 498
Macro or Micro Constants, 421
MacroToMicro, 422, 432, 433, 434, 452, 455, 458, 462,
Fitting, 443
466, 476, 479, 484, 488, 494, 500
Missing, 115, 154, 160
MakeConcUnit, 76, 81, 83, 337, 360, 373, 451, 457, 460,
464, 467, 470, 474, 477, 481, 485, 490, 497, 517, 529, 540 Model Validation, 726
Marquardt's Principle Models, 258

Fitting, 443
Models and Notation, 720
Mean Curve, 45, 46, 191, 199, 200, 201, 202, 210
Modifying Your Graphs, 218
Merge Results, 133, 147, 157
Multiple Dose, 424, 426, 427, 428, 429, 430, 438, 449,
Message Box, 9 450, 481, 482, 485, 487, 490, 492, 496, 499
Fitting, 424
Method Editor, 48
Multiplying Units, 87
Methodological Background, 719
Methodology

Index
N Population Designer, 652
Population Parameter Estimates

NCA Assistant, 42, 336, 402, 407, 411
Sparse Data Situation, 722
Non-Compartmental Analysis, 4, 327, 336
Population validation, 636
Non-Detectable Data, 223
Power model, 620
Normal Kinetica Template, 66
P-Pharm, 157, 165
Profile Properties, 193, 234

O Protecting Kinetica Datasets, 58, 59
Observed Concentration Units, 76 Protein Binding, 4
Obtaining Simplified Units, 90
ODBC, 106, 142, 144, 168

R
Opening an Existing Kinetica File, 65
Rate Units, 82
Opening an Existing Kinetica Template, 68
Remove All Methods, 27
Outlier, 115, 153, 160, 220, 402, 408
Remove Last Method, 26
Output Data, 9
Reports Pane, 49
Residuals, 445, 448, 451, 456, 459, 462, 466, 469, 472,
476, 480, 484, 485, 489, 491, 495, 496, 497, 501, 518, 519,
P 530, 531, 540, 541
PCNonlin, 41, 165, 167 Running population validation using the concentration
method with covariable, 647
PD Analysis
Fitting, 502 Running population validation using the parameter
method, 637
Performing statistical analysis, 657
Pharm-ABS, 165
Pharmacokinetic/Pharmacodynamic, 513
S
Save As Graph Template, 235
PK Template Examples, 449
Save Graph As, 242
PK/PD Fitting, 260
Save Table Script Files, 572
Plasma View, 67, 509
Saving a File as an Empty Kinetica Template, 71
Plotting Mean Curves, 204
Saving a Gallery Inside a KDB File, 237
Plotting the Residuals, 456, 459, 462, 466, 469, 472, 476,
480, 484, 489, 495, 501

Index
Saving a Gallery to File, 235 Standardized Concentration Prediction Error, 726
Saving Graphs, 241, 242 Standardized Parameter Prediction Error, 727
Saving Kinetica Files, 70 Statistical Analysis

Latin Square with Greater Than Two Formulations,
Schwartz criterion, 725
680
Script Files, 573 Statistics and Goodness of Fit
Fitting, 445
Send to Gallery, 194, 233, 417
Status Column, 115, 116, 140, 154, 160
Set Column Unit, 80, 85, 86, 89, 90, 337, 350, 360, 373,
451, 457, 460, 464, 467, 470, 474, 477, 481, 485, 490, 497, Stepwise Regression, 737
507, 517, 529, 540
Stripping
Set Column Unit Method, 80
Fitting, 441
Show Points Legend, 193, 234 Stripping, Failure of
Fitting, 441
Show Sets Legend, 193, 234, 235
Student t test, 715
Show Status Legend, 235
Study Group, 19, 166, 191, 199
Sigmoid, 505, 506
Study Icon, 45, 193, 200, 234, 235
Simple Hard-Coded Methods, 260
Study Info, 45
Simplex Method, 729
Study Objects, 45
Simplified Units, 90
Study Pane, 45
Single Dose Extravascular Macro Constants Template,
456 Study Variables, 45
Fitting, 456
Single Dose Zero Order Input Macro Constants
Template, 451 T
Fitting, 451
Table Assistant, 42, 48, 549, 550, 568, 573
SIPHAR, 165
Table Info, 48
Soft-Coded Methods, 258
Tables Group, 48
Source Columns, 132, 133, 135, 137, 147, 149, 157
Tables Pane, 48
Spaghetti Plot, 45, 191, 196, 197
Template Examples, PK, 449
Sparse Data
Population Parameter Estimates, 722 templates, 4
Specifying Units, 75 Templates, 64, 230
Spreadsheet Interface, 52

Index
Termination Criteria, 735 Z

Ticks, 218, 219
Zero Order Absorption, 429, 515
To Adjust All Columns & Rows, 52
To Adjust Individual Columns & Rows, 52
To Format Cells, 52
Toolbar, 41
U
Undetectable, 115, 153, 159, 410
Unit Configuration, 73
Unit Management for AUC*, AUCinter* or AUC

Steady State* Methods, 90
V
VBA Editor, 45, 48
Viewing Mean Curves Without Statistics, 201, 202
W
Weighted Residuals, 445, 448, 451, 456, 459, 462, 466,
469, 472, 476, 480, 484, 486, 489, 491, 495, 497, 501, 518,
519, 530, 531, 540, 541
Weighting Schemes
Fitting, 442
WinNonlin, 165
Word, 43
X
XPD, 165
XY Unit, 88

Thermo Fisher Scientific
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Massachusetts 02454-9046
United States
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Part Number KIN-UM-5.0

Revision Number 1.00

Software Version Kinetica 5.0

Thermo Fisher Scientific Kinetica User Manual i

ii Kinetica User Manual Thermo Fisher Scientific

Thermo Fisher Scientific Kinetica User Manual iii

5. Importing and Exporting Data ............................................... 97

iv Kinetica User Manual Thermo Fisher Scientific

7. Methods and Models .......................................................... 257

Thermo Fisher Scientific Kinetica User Manual v

9. Performing Compartmental Analysis ................................. 419

vi Kinetica User Manual Thermo Fisher Scientific

11. Population Pharmacokinetics (PK) .................................... 575

Thermo Fisher Scientific Kinetica User Manual vii

viii Kinetica User Manual Thermo Fisher Scientific

Each Kinetica analysis is comprised of results computed using

From non-compartmental to population PK/PD analyses,

Thermo Fisher Scientific Kinetica User Manual 1

• The Kinetica Basic Reference Guide, a self-contained manual

This user guide is also available in WinHelp format; access it by

2 Kinetica User Manual Thermo Fisher Scientific

Understanding Kinetica is a template-driven system that provides standardized

The organization of Kinetica templates and methods is made

Thermo Fisher Scientific Kinetica User Manual 3

Kinetica Templates A template is a collection of methods created and saved as an

Kinetica templates offer several advantages:

• High consistency between analyses and between users.

• Time savings by not having to validate each user’s analysis.

• Version control between analyses of the same study.

Kinetica is installed with nine subdirectories containing validated

• In Vivo/In Vitro Correlation

Some of the templates that were previously accessed from the

4 Kinetica User Manual Thermo Fisher Scientific

• In Vitro/In Vivo Correlation

Thermo Fisher Scientific Kinetica User Manual 5

Kinetica Methods A method is a default or user-defined calculation, which

Kinetica provides a library of pre-defined methods and models

6 Kinetica User Manual Thermo Fisher Scientific

Thermo Fisher Scientific Kinetica User Manual 7

Setting up Reports During analysis various information is calculated, messages are

Figure 1-1. Report Setup Dialog, Sample Configuration

The different report types available in Kinetica (as shown in

Output Use in Kinetica

Report Automatically-generated text summary of methods

8 Kinetica User Manual Thermo Fisher Scientific

Output Use in Kinetica

Error Short text output altering you to errors encountered

Message Messages are generally warnings generated during

Table Table output is only generated via user interaction.

Destination Destination Action

Message Displays the selected output in a message box.

Nothing Does not display or write any information.

Thermo Fisher Scientific Kinetica User Manual 9

Destination Destination Action

Word 6/95 Links the Report output type to Microsoft Word.

This option does not automatically load

Word 97 Links the Report output type to Microsoft Word

This option automatically finds, and then loads

10 Kinetica User Manual Thermo Fisher Scientific

Destination Destination Action