Non-compartmental analysis

and
The Mean Residence Time approach

1
 Synonymous

Mean Residence Time approach

Statistical Moment Approach
Non-compartmental analysis

2
 Statistical Moments

Describe the distribution of a random variable :

location, dispersion, shape ...

Standard deviation

Mean Random variable values 3

 Statistical Moment Approach

Stochastic interpretation of drug disposition

Individual particles are considered : they are assumed to
move independently accross kinetic spaces according to
fixed transfert probabilities
The time spent in the system by each particule is considered
as a random variable
The statistical moments are used to describe the distribution
of this random variable, and more generally the behaviour of
drug particules in the system 4
 Statistical Moment Approach

C t dt
n
n-order statistical moment t
0

t C t dt C t dt AUC
0
zero-order :
0 0

one-order : t C t dt AUMC
0 5
 Statistical Moment Approach

Statistical moments in pharmacokinetics.

J Pharmacokinet Biopharm. 1978 Dec;6(6):547-58.
Yamaoka K, Nakagawa T, Uno T.

Statistical moments in pharmacokinetics: models and assumptions.

J Pharm Pharmacol. 1993 Oct;45(10):871-5.
Dunne A.

6
The Mean Residence Time

7
 Mean Residence Time

Principle of the method: (1)

Entry : time = 0, N molecules
Evaluation of the time each molecule of a
dose stays in the system: t1, t2, t3tN

MRT = mean of the different times

MRT = t1 + t2 + t3 +...tN
N

Exit : times t1, t2, ,tN 8

 Mean Residence Time

Principle of the method : (2)

Under minimal assumptions, the plasma

concentration curve provides information on the
time spent by the drug molecules in the body

9
 Mean Residence Time

Principle of the method: (3)

Entry (exogenous, endogenous)

Central
compartment recirculation
(measure) exchanges

Exit (single) : excretion, metabolism

Only one exit from the measurement compartment

First-order elimination : linearity 10
 Mean Residence Time

Principle of the method: (4)

N molecules administered in the system at t=0
The molecules eliminated at t1 have a residence time in the system
equal to t1
Consequence of linearity
AUCtot is proportional to N
C
Number n1 of molecules eliminated at t1+ t is
proportional to AUCt:
C1
AUCt C(t1) x t
n1 = XN = XN
AUCtot AUCtot
t1 (t) 11
 Mean Residence Time
Principle of the method: (5)
C Cumulated residence times of
molecules eliminated during t at :
C1
Cn t1 : t1 x C(1) x tx N n1
AUCTOT
C(n) x t
t1 tn (t) tn : tn x AUC x N
TOT

C1 x t x N Cn x t x N
MRT = t1x tn x N
AUCTOT AUCTOT
12
 Mean Residence Time
Principle of the method: (5)
C1 x t x N Cn x t x N
MRT = t1x tn x N
AUCTOT AUCTOT

MRT = t1x C1 x t tn x Cn x t AUCTOT

ti x Ci x t t C(t) t AUMC
MRT = = =
AUCTOT C(t) t AUC
13
 Mean Residence Time

AUMC
MRT
AUC

AUC C t dt
0

AUMC t C t dt
14
0
 AUC = Area Under
the zero-order
moment Curve
AUMC
AUMC = Area
Under the first-
order Moment
AUC
Curve

From: Rowland M, Tozer TN. Clinical Pharmacokinetics Concepts and Applications, 15

3rd edition, Williams and Wilkins, 1995, p. 487.
 Mean Residence Time

Limits of the method:

Central
compartment
(measure)

2 exit sites
Statistical moments obtained from plasma concentration
inform only on molecules eliminated by the central
compartment
16
 Computational methods

Non-compartmental analysis Area

calculations
Trapezes

Fitting with a poly-exponential equation

Equation parameters : Yi, li

Analysis with a compartmental model

Model parameters : kij
17
 Computational methods
Area calculations by numerical integration

1. Linear trapezoidal
C
1

Ci Ci1
C

t
2
AUC i t i 1 Concentration
i 2

t
1
t
2

t i Ci t i1 Ci1
AUMC i i1
i
t t
2
Time

18
 Computational methods
Area calculations by numerical integration

1. Linear trapezoidal

Advantages: Simple (can calculate by hand)

Disadvantages:
Assumes straight line between data points
If curve is steep, error may be large
Under or over estimation, depending on whether the
curve is ascending of descending
19
20
 Computational methods
Area calculations by numerical integration

2. Log-linear trapezoidal
C
Ci Ci 1
1
C

t i t i1
2
Concentration
Ln Ci
AUC i

C i 1
t
1
t
2

Time
AUMC

21
 Computational methods
Area calculations by numerical integration

2. Log-linear trapezoidal < Linear trapezoidal

Advantages:
Hand calculator
Very accurate for mono-
exponential
Very accurate in late time points
where interval between points is
substantially increased
Disadvantages:
Produces large errors on
an ascending curve, near
the peak, or steeply
declining polyexponential
curve

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 Computational methods

Extrapolation to infinity

C t dt
Clast Assumes log-
AUC t
la st
tla st
lz linear decline

Clast tlast Clast

AUMC t
last
l2
z lz
23
 Computational methods

AUC Determination AUMC Determination

Cxt Area
Time (hr) C (mg/L) Area (mg.hr/L) (mg/L)(hr) (mg.hr2/L)
0 2.55 - 0 -
1 2.00 2.275 2.00 1.00
3 1.13 3.13 3.39 5.39
5 0.70 1.83 3.50 6.89
7 0.43 1.13 3.01 6.51
10 0.20 0.945 2.00 7.52
18 0.025 0.900 0.45 9.80
Total 10.21 37.11
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 Non-compartmental analysis

The Main PK parameters can be calculated using non-compartmental

analysis

MRT = AUMC / AUC

Clearance = Dose / AUC

Dose x AUMC
Vss = Cl x MRT =
AUC2
F% = AUC EV / AUC IV DEV = DIV
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 Computational methods

Non-compartmental analysis Area

calculations
Trapezes
Fitting with a poly-exponential equation Area
Equation parameters : Yi, li calculations

Analysis with a compartmental model

Model parameters : kij
26
 Fitting with a poly-exponential equation

Area calculations by mathematical integration

n
C(t) Yi e i t For one compartment :
i 1

n
Yi C0
AUC AUC
i 1 i
k10 1
MRT
k10
Yi n C0
AUMC 2 AUMC 2
i 1 i
k10
27
 Fitting with a poly-exponential equation

For two compartments : C(t) Y1 e 1t Y2 e 2 t

Yi Y1 Y2
AUC AUC
li l1 l2

Yi Y1 Y2
AUMC AUMC
l 2
i l2
1 l22
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 Computational methods
Area
Non-compartmental analysis calculations
Trapezes
Fitting with a poly-exponential equation Area
Equation parameters : Yi, li calculations

Analysis with a compartmental model Direct MRT

Model parameters : kij calculations
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 Analysis with a compartmental model
Example : Two-compartments model
k12

1 2
k21
k10

k10 k12 X1
dX1
k 21 X 2
dt
dX 2
k12 X1 - k 21 X 2
dt 30
 Analysis with a compartmental model
Example : Two-compartments model
K is the 2x2 matrix of the system of differential equations
describing the drug transfer between compartments

X1 X2

dX1/dt k10 k12 k 21

K=
dX2/dt k12 - k 21
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 Analysis with a compartmental model

Then the matrix (- K-1) gives the MRT in each compartment

Dosing in 1 Dosing in 2

Comp 1 MRTcomp1 MRTcomp1

(-K-1) =
Comp 2 MRTcomp2 MRTcomp2

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 The Mean Residence Times

Fundamental property of MRT : ADDITIVITY

The mean residence time in the system is the sum of the

mean residence times in the compartments of the system

Mean Absorption Time / Mean Dissolution Time

MRT in central and peripheral compartments
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The Mean Absorption Time
(MAT)

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 The Mean Absorption Time

Definition : mean time required for the drug to reach the central
compartment

EV IV
Ka
A 1 K10
F = 100%

AUMC AUMC AUMC

MRTsystem comp. A 1 MRTcomp. A
AUC EV AUC EV AUC IV

AUMC MRTcomp. A MAT

MRTcomp 1 !
AUC IV 35
because bioavailability = 100%
 The Mean Absorption Time

MAT and bioavailability

!
Actually, the MAT calculated from plasma data is
the MRT at the injection site

This MAT does not provide information about the

absorption process unless F = 100%

Otherwise the real MAT is : MRTcomp. A

MAT
F
36
 The Mean Dissolution Time
In vivo measurement of the dissolution rate in
the digestive tract
tablet solution

dissolution absorption
solution

digestive tract blood

MDT = MRTtablet - MRTsolution 37

 Mean Residence Time in the
Central Compartment (MRTC) and in
the Peripheral (Tissues)
Compartment (MRTT)

38
 MRTcentral and MRTtissue

Entry

MRTC MRTT MRTsystem = MRTC + MRTT

Exit (single) : excretion, metabolism

39
The Mean Transit Time
(MTT)

40
 The Mean Transit Times (MTT)

Definition :
Average interval of time spent by a drug particle from its
entry into the compartment to its next exit
Average duration of one visit in the compartment
Computation :
The MTT in the central compartment can be calculated
for plasma concentrations after i.v.

41
The Mean Residence Number
(MRN)

42
 The Mean Residence Number (MRN)

Definition :
Average number of times drug particles enter
into a compartment after their injection into the
kinetic system
Average number of visits in the compartment
MRT
For each compartment : MRN =
MTT
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 Stochastic interpretation of the drug
disposition in the body

Mean number
R+1 R
of visits
IV
Cldistribution
MRTC MRTT
(all the visits) R (for all the visits)
MTTC number MTTT
of cycles
(for a single visit) (for a single visit)
Clredistribution
Clelimination 44
 Stochastic interpretation of the drug
disposition in the body
Computation : intravenous administration
MRTsystem = AUMC / AUC

MRTC = AUC / C(0) MRTT = MRTsystem- MRTC

MRTC
MTTC = - C(0) / C(0) R+1=
MTTC

MRTT
MTTT =
R
45
 Interpretation of a Compartmental Model
Determinist vs stochastic
Digoxin
21.4 e-1.99t + 0.881 e-0.017t
Cld = 52 L/h
0.3 h MTTC : 0.5h MTTT : 10.5h
4.4
MRTC : 2.81h MRTT : 46h
41 h
Vc 34 L ClR = 52 L/h VT : 551 L
stochastic
Cl = 12 L/h
Determinist
1.56 h-1
Vc : 33.7 L VT : 551L MRTsystem = 48.8 h
0.095 h-1
0.338 h-1
46
t1/2 = 41 h
 Interpretation of a Compartmental Model
Determinist vs stochastic
Gentamicin
y =5600 e-0.281t + 94.9 e-0.012t Cld = 0.65 L/h
t1/2 =3h MTTC : 4.65h MTTT : 64.5h
0.265
t1/2 =57h MRTC : 5.88h MRTT : 17.1h
Vc : 14 L ClR = 0.65 L/h VT : 40.8 L
stochastic
Cllimination = 2.39 L/h
Determinist
0.045 h-1
Vc : 14 L VT : 40.8L MRTsystem = 23 h
0.016 h-1
0.17 h-1
47
t1/2 = 57 h
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The purpose of a PBPK model is to define the relationship between an
external measure of (administered) exposure/dose and an internal
measure of biologically effective) exposure /dose in (gy )p / both the
experimental animal and the human

52
 Applications of PBPK Modeling

Chemical risk assessment

Drug development research and evaluation

Interpretation of human biomonitoring data

In vitro to in vivo extrapolation Invitro to in vivo
extrapolation

Evaluation of early -life susceptibility
53
 How are PBPK Models Used
in Human Health Risk Assessment?
Assess the biological determinants that govern the kinetic behavior

Calculate tissue dose metrics for risk assessment calculations

Support extrapolation across dose-routes, between species, from high to low dose
levels, and over various dosing scenarios

Assess mechanisms of response (PD) based on their relationship with dose
metrics for target tissues

54
 Applications of PBPK Models in Drug
Development Research and Evaluation
Integrate information from different studies Different routes of exposure
Different species Different dosing regimens

Provide a validated platform for predictive simulation of alternative

dosing methods drug-drug interactions (DDI)

Improve understanding of PD by relating effect to dose at target tissue or

binding to target protein (PBPK/PD)

Support more accurate estimation of equivalent human dosing to achieve

same dose to target protein as in test animals

Predict fetal exposure and lactation transfer

Estimate variability of PK across special populations

Obese, Elderly, Infants, Diseases
Polymorphisms
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