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A Recirculatory Model for Pharmacokinetics and

the Effects on Bispectral Index After Intravenous


Infusion of the Sedative and Anesthetic AZD3043
in Healthy Volunteers
Marcus A. Bjrnsson, MSc Pharm, PhD,* ke Norberg, MD, PhD, Sigridur Kalman, MD, PhD,
and Ulrika S. H. Simonsson, MSc Pharm, PhD

BACKGROUND: AZD3043 is a positive allosteric modulator of the -aminobutyric acid type


A receptor, with sedative and anesthetic properties. We describe a population pharmacoki-
netic (PK) model of arterial and venous concentrations of AZD3043 and the pharmacodynamic
effects on bispectral index (BIS) in healthy volunteers.
METHODS: Arterial and venous plasma concentrations of AZD3043 and BIS were measured
in 2 clinical studies in 125 healthy volunteers, where AZD3043 was given as a 1-minute bolus
(16 mg/kg), a 30-minute infusion (181 mg/kg/h), or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40
(mg/kg bolus + mg/kg/h infusion for 30 minutes). Population PK/pharmacodynamic analysis
was performed with NONMEM.
RESULTS: A recirculatory model, comprising a series of 5 compartments for the transit of drug
between venous and arterial plasma, 2 peripheral distribution compartments, and 1 compart-
ment for the nondistributive transit of drug from arterial to venous plasma, described the PK of
AZD3043. Systemic clearance was high (2.2 L/min; 95% confidence interval, 2.122.25), and
apparent volumes of distribution were low, leading to a short elimination half-life. The apparent
volumes of distribution of the arterial and peripheral compartments increased with increasing
administered dose, giving a total apparent volume of distribution of 15 L after the lowest dose
and 37 L after the greatest dose. A sigmoid maximum effect (Emax) model with an EC50 of 15.6
g/mL and a of 1.7 described the relationship between AZD3043 effect-site concentrations
and BIS. The between-subject variability in EC50 was 37%. An effect compartment model, with a
half-life of the equilibration rate constant ke0 of 1.1 min, described the delay in effect in relation
to the arterial plasma concentrations.
CONCLUSIONS: AZD3043 had a high clearance and a low apparent volume of distribution,
leading to a short half-life. However, the apparent volume of distribution was dose dependent
(P<0.001), leading to an increased half-life with increasing dose. The distribution to the effect
site was fast and together with the short plasma half-life led to a fast onset and offset of
effects. (Anesth Analg 2015;121:90413)

A
n easily controllable depth of anesthesia is an impor- AZD3043, originally called THRX-918661, is a posi-
tant property for a new anesthetic compound. This tive allosteric modulator of the -aminobutyric acid type
could be achieved with a short half-life, resulting A receptor, with sedative and anesthetic properties.3 It is
from rapid metabolism and a low volume of distribution, metabolized by esterases in plasma and the liver, leading
and rapid equilibration between blood and the site of action. to a high systemic clearance and a short half-life. In 2 clini-
Pharmacokinetic (PK)/pharmacodynamic (PD) modeling is cal studies in healthy volunteers, AZD3043 induced seda-
a useful tool to assess these properties.1 A quantitative mea- tion and anesthesia in a dose-dependent manner, and the
sure of the depth of anesthesia, to be used for guiding the dos- subjects recovered rapidly after the end of the AZD3043
ing of the anesthetic, can be obtained by the bispectral index infusions.4,5
(BIS), which is derived from the electroencephalogram.2 The aims of this analysis were to describe the population
PK of arterial and venous AZD3043 concentrations with a
From the *Quantitative Clinical Pharmacology, AstraZeneca R&D, recirculatory model and the relationship between AZD3043
Sdertlje, Sweden; Department of Pharmaceutical Biosciences, Uppsala concentrations and the effect on BIS in healthy volunteers,
University, Uppsala, Sweden; Department of Clinical Science Intervention
and Technology, Karolinska Institutet, Stockholm, Sweden; and Department including potential covariate (COV) effects of body weight,
of Anesthesiology and Intensive Care, Karolinska University Hospital, sex, age, and esterase activity.
Huddinge, Sweden.
Accepted for publication April 5, 2015. METHODS
Funding: This study was funded by AstraZeneca R&D. Study Designs
Conflict of Interest: See Disclosures at the end of the article. This analysis was performed with data from the first 2 clini-
Reprints will not be available from the authors. cal studies of AZD3043 in healthy volunteers (clinicaltrials.
Address correspondence to Ulrika S. H. Simonsson, MSc Pharm, PhD, De- gov identifiers NCT00918515 and NCT00984880).4,5 Both
partment of Pharmaceutical Biosciences, Uppsala University, Uppsala, Swe-
den. Address e-mail to ulrika.simonsson@farmbio.uu.se. studies were performed at Karolinska University Hospital,
Copyright 2015 International Anesthesia Research Society
Huddinge, Sweden, in accordance with the Declaration
DOI: 10.1213/ANE.0000000000000814 of Helsinki and Good Clinical Practice. The studies were

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approved by the Regional Independent Ethics Committee Unbound AZD3043 concentrations were measured in the
in Stockholm, Sweden, and the Swedish Medical Products venous samples obtained at 29 and 40 minutes after start of
Agency, and written informed consent was obtained from infusion in the first study. In both studies, BIS (BIS VISTA,
all subjects. Aspect Medical Systems, Inc., Norwood, MA) was elec-
The first study4 was a dose-escalation study, where tronically captured every minute until the subjects were
30-minute constant rate IV infusions of 1, 3, 6, 12, 18, 27, 36, awake according to the clinical signs, including Modified
54, or 81 mg/kg/h were given to 53 healthy male volun- Observers Assessment of Alertness/Sedation scale.9
teers. There were 6 subjects per group except for the 1-mg
group, where there were 5 volunteers. All subjects had nor- Data Analysis
mal plasma butyrylcholinesterase activity, as measured with Nonlinear mixed effects modeling was performed with
the dibucaine number test.6,7 Subject demographics are pre- NONMEM 7.2 (ICON Development Solutions, Ellicott
sented in Table1. Arterial and venous plasma samples were City, MD).10 The first-order conditional estimation method
obtained before start of infusion and at 2, 5, 15, 29, 31, 32, 35, with interaction was used for all estimations. Perl speaks
37, 40, 45, 60, 75, 90, and 120 minutes after start of infusion. NONMEM (PsN)11 was used for automating and control-
In addition, venous plasma samples were obtained at 4.5, 8, ling runs, and Xpose 412 and R (http://www.r-project.org)
and 24 hours after start of infusion. were used to produce goodness-of-fit graphics, including
The second study5 was divided into 2 parts. In part A, visual predictive checks (VPCs).
each subject received a 1-minute IV bolus of 1, 1.5, 2, 4, or The modeling was performed sequentially, starting with
6 mg/kg. In part B, each subject received 0.8 + 10, 1 + 15, 3 the PK model, followed by the analysis of BIS. Models were
+ 30, or 4 mg/kg bolus + 40 mg/kg/h 30-minute infusion. selected based on the goodness-of-fit plots, precision in
Different subjects were included in the 2 parts, i.e., each parameter estimates, and statistically using the objective
subject received only 1 treatment. Seventy-two healthy vol- function value (OFV). A decrease in OFV by 6.63 (corre-
unteers (men or women of nonchildbearing potential, with sponding to a P value <0.01) was required for a parameter
normal plasma butyrylcholinesterase activity), 8 subjects to be included in the model. Confidence intervals of the
per group, were included in the study (Table1). Arterial and parameters were obtained from nonparametric bootstraps
venous plasma samples were collected and analyzed for with 1000 samples, implemented in PsN. Because the
AZD3043 as described previously, before start of infusion, at range of doses was large and every individual was dosed
50 to 55 seconds (before stop of 1-minute infusion); at 1, 4, 14, based on their body weight, VPC was normalized by the
and 29 minutes during the 30-minute infusion (part B); and population predictions (PREDs) for each individual via the
at 1, 4, 6, 9, 14, 29, 44, 59, and 119 minutes after the end of the
PRED-corrected VPC (PC-VPC) in PsN.13 In a PC-VPC, each
1-minute (part A) or 30-minute (part B) infusion. In addition,
observed or simulated value is divided by the correspond-
venous samples were also collected at 4 hours after stop of
ing PRED for that individual at that time and multiplied
infusion and at 8 and 24 hours after start of infusion.
by the median PRED of all individuals, regardless of dose,
The number of patients included in these exploratory
in that time-bin. That way all data are normalized to fit on
studies was not determined based on any statistical con-
the same scale while the shape of the curve is maintained.
siderations but rather on previous experience with similar
Log-likelihood profiles for the PK parameters were created
studies. In a survey of 105 first-in-human studies published
by fixing the parameters, 1 at a time, to different values and
between 1995 and 2004,8 the most common number of sub-
re-estimating the other parameters. The difference in OFV
jects on active treatment per cohort was 6, as in the first
was then plotted versus the value of the fixed parameter.
study of this work. In the second study included in this
Log-normal distribution of the parameters around the
work, the number of subjects was increased to 8.
typical value was assumed:
All samples from both studies were collected in the
presence of stabilizers to avoid ester-induced hydrolysis of
Pi = P exp(i )
AZD3043 and analyzed for total AZD3043 concentrations
by Huntingdon Life Sciences Ltd, Huntingdon, United
Kingdom, by the use of liquid chromatography with tan- where Pi is the value of the parameter in individual i, P is the
dem mass spectrometry. The method was validated over typical value of the parameter in the population, and i is
the concentration range 0.01 to 20 g/mL, and the over- the normally distributed interindividual random variability
all mean precision (percent coefficient of variation, or with mean 0 and variance 2. Additive, proportional, and
%CV) and accuracy (%Bias) for the QC samples at 3 con- combined additive and proportional residual error models
centrations in plasma were 8.4% and 4.6%, respectively. were investigated.

Table 1.Descriptive Statistics of Demographics and Covariates


n Age (y) Sex (M/F) Body weight (kg) BMI (kg/m2) Dibucaine numbera
Study 1 53 25 (1842) 53/0 (100/0) 76 (5796) 24 (1930) 134 (89192)
Study 2 70b 31 (2065) 62/8 (89/11) 77 (5498) 24 (1930) 131 (77182)
Total 123b 28 (1865) 115/8 (93/7) 77 (5498) 24 (1930) 133 (77192)
Data for sex are represented as n (%). Other data are represented as median (range).
BMI = body mass index; F = female; M = male.
a
Dibucaine numbers >70 were considered normal.7
b
Two subjects were excluded from the analysis because of interruptions in the infusions and are not included in this table.

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Recirculatory Pharmacokinetics and Pharmacodynamics of AZD3043

Median prediction error (MDPE) and median absolute fit was found. Drug elimination was assumed to occur from
performance error (MDAPE) were calculated for the final the arterial compartment, but elimination from the venous
models according to Varvel et al.14 Plasma concentrations compartment also was assessed. Thereafter, the effect of
that were less than the limit of quantification (0.01 g/mL) dose, accumulated administered dose, and concentration
were excluded from the analysis. In case the concentra- on the clearance and apparent volume of distribution were
tions increased after observations below the limit of quan- evaluated. The influence of body weight on clearance and
tification, these samples were also excluded. In 4 subjects volume parameters was then assessed by having them not
in study 1 and in 16 subjects in study 2, unexpected, and scaled to body weight, directly proportional to body weight,
sometimes large, increases in venous concentrations were or scaled allometrically to body weight (normalized to the
observed at late time points, likely due to sampling errors median value 77 kg), where the volume parameters were
(sample contamination by initial dose) because the corre- assumed to be directly proportional to body weight, while
sponding metabolite concentrations did not increase. These the elimination and intercompartmental clearance param-
samples were regarded as artifacts and were not included eters were related to body weight raised to the power 0.75.15
in the analysis. In 2 subjects, there were BIS values that sud- Finally, the effects of esterase activity, sex, and age on clear-
denly decreased to 0 at the exact times of several arterial ance were investigated. COVs were modeled as linear rela-
blood pressure measurements. These values were regarded tions, centered at the median value of the COV:
as artifacts and were excluded from the analysis. Two sub-
jects in the second study were excluded from all analyses P = 1 (1 + 2 ( COV COVmedian ) )
because there were interruptions in the infusions, and there-
fore, the exact dosing history was not known. This means
that the total number of subjects included in the analysis where 1 is the typical value of parameter P for an indi-
was 123. In 2 subjects, sudden transient increases in BIS to vidual with the median value of a COV (COVmedian), and 2
high values were seen during infusion while the subjects is the fractional change in the parameter for each unit the
were deeply anesthetized. These increased values were COV differs from the median. For the categorical COV, sex,
regarded as artifacts and were excluded from the analysis. the effect on clearance was modeled as a fractional change
between male and female volunteers.
PK Analysis
A recirculatory PK model was developed and fitted to arte- PD Analysis
rial and venous concentrations simultaneously. The model When developing the BIS model, the PK parameters (both
consisted of an arterial and a venous compartment, periph- fixed and random effects) were fixed to their estimates from
eral distribution compartments, a tanks-in-series transit the final PK model and the PK data were retained in the
representing the transport of drug through the heart and dataset.16 This approach conditions the PD analysis not only
lungs, and a nondistributive pathway between arterial on the PK parameters but also on the PK data, accounting for
and venous plasma (Fig.1). First, the structural model was uncertainty in the individual predictions of the PK param-
identified by increasing the number of compartments in the eters. An effect-compartment model was used to describe
central circulation, the nondistributive pathway, and the the delay of effects on BIS in relation to the arterial plasma
peripheral distribution until no further improvement of the concentrations of AZD3043. The rate constant of the effect

Figure 1. Schematic representation of


the final recirculatory pharmacokinetic
model. CL = elimination clearance;
ke0 = rate constant for equilibration
between plasma and effect-site concentra-
tion; QCO = cardiac output (plasma flow);
QND = plasma flow of nondistributive
pathway; QP1 = plasma flow through
peripheral compartment 1; QP2 = plasma
flow through peripheral compartment
2; VA = arterial volume; VV = venous vol-
ume; VC = volume of central circulation;
VP1 = volume of peripheral compartment 1;
VP2 = volume of peripheral compartment 2.

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delay was described by the parameter ke0. A 2-compartment From the arterial plasma, with the volume VA, the drug
effect-site model17 also was tested, in which distribution is transferred to the venous plasma, with the volume VV,
was assumed to occur from the effect-site compartment to through 2 peripheral distribution compartments with the
peripheral parts of the brain. The effect-site concentrations apparent volumes VP1 and VP2 and 1 compartment for the
were related to BIS by a linear model, a maximum effect nondistributive transit. The plasma flow through the non-
(Emax) model, and a sigmoid Emax model, according to the distributive and distribution compartments is represented
following equation: by QND, QP1, and QP2. In the final model, elimination clear-
ance occurred from the arterial compartment. Plasma clear-
E Ce ance was high (2.2 L/min), which was as much as 76% of the
BIS = Baseline 1 max
estimated cardiac output (plasma flow), with low between-
EC50 + Ce
subject variability (14%). The effect of body weight on the
parameters was best described by an allometric model. No
where Baseline is the BIS before start of drug administra- significant effects (P > 0.1) of dose, esterase activity, sex, or
tion, Emax is the maximum effect (in this analysis fixed to 1 age on clearance were found. The arterial and the peripheral
as very low BIS values were observed), EC50 is the effect- apparent volumes of distribution increased with increasing
site concentration needed to achieve 50% of the maximum administered dose. Total apparent volume of distribution
effect, Ce is the concentration at the effect site, and is a (the sum of the distribution volumes in the arterial, venous,
shape factor. The effects of sex, age, and body weight on central, and peripheral compartments at the end of infu-
EC50 were investigated. The criteria for including a COV in sion) was 15 L in the lowest dose group (receiving a total
the model were the same as for the PK analysis. dose of 0.5 mg/kg) and increased with increasing infused
dose up to 37 L in the greatest dose group (40.5 mg/kg).
RESULTS Shrinkage was <30% for all PK parameters except VV (31%)
Pharmacokinetics and QCO (49%). A high shrinkage implies that there is lim-
Observed and predicted arterial and venous concentrations ited information of a parameter in some individuals, and
of AZD3043, stratified by the different dose groups, are therefore, their individual estimates of the parameters are
presented in Figures2 and 3, respectively. During the infu- shrunk toward the population mean. For example, in the
sions, arterial concentrations were greater than venous con- case of oral absorption, a patient with only samples late in
centrations, whereas after the end of the infusions, venous the elimination phase will provide no information on the
concentrations were greater than arterial concentrations absorption parameters and that patients individual predic-
(Fig.4). The unbound fraction of AZD3043 increased with tions of the absorption parameters will be the population
increasing concentrations, from 5% to 12% in the lowest mean. The population parameters for absorption may still
dose group to 18% to 30% in the greatest dose group. be well estimated if other individuals provide data on the
A recirculatory model was used to fit arterial and venous absorption phase. If shrinkage is high, goodness-of-fit plots
plasma concentrations of AZD3043 simultaneously (Fig.1). using individual predictions may be less useful.18
The final model consisted of a series of a 5 tanks-in-series Key modeling steps are listed in Table2. The parameter
transit of drug from venous plasma, where the drug was estimates for the final PK model are presented in Table 3.
administered, to arterial plasma. This represents the central The PC-VPC for the final PK model, stratified for arterial
circulation, described by the cardiac output (QCO) and a cen- and venous plasma and the 3 different dosing regimens,
tral apparent volume of distribution (VC). The cardiac out- is shown in Figure5, and the plots of observed divided by
put was not measured in the studies but rather estimated as population predicted concentrations over time are shown
a plasma flow based on the limited sampling of AZD3043. in Figure6. MDPE and MDAPE are summarized in Table4.

1 mg/kg/h 3 mg/kg/h 6 mg/kg/h 12 mg/kg/h 18 mg/kg/h 27 mg/kg/h

100
Arterial Concentration (ug/mL)

10
1
0.1
36 mg/kg/h 54 mg/kg/h 81 mg/kg/h 1 mg/kg bolus 1.5 mg/kg bolus 2 mg/kg bolus

100
10
Figure 2. Individual observed (blue)
1
and typical predicted (red) arterial
0.1 plasma concentrations of AZD3043
4 mg/kg bolus 6 mg/kg bolus 0.8 mg/kg + 10 mg/kg/h 1 mg/kg + 15 mg/kg/h 3 mg/kg + 30 mg/kg/h 4 mg/kg + 40 mg/kg/h versus time, stratified for different
100 dosing regimen.
10
1
0.1

0 30 60 90120 0 30 60 90120 0 30 60 90120 0 30 60 90120 0 30 60 90120 0 30 60 90120

Time (min)

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Recirculatory Pharmacokinetics and Pharmacodynamics of AZD3043

1 mg/kg/h 3 mg/kg/h 6 mg/kg/h 12 mg/kg/h 18 mg/kg/h 27 mg/kg/h

100
Venous Concentration (ug/mL)

10
1
0.1
36 mg/kg/h 54 mg/kg/h 81 mg/kg/h 1 mg/kg bolus 1.5 mg/kg bolus 2 mg/kg bolus

100
10
Figure 3. Individual observed (blue)
1
and typical predicted (red) venous
0.1 plasma concentrations of AZD3043
4 mg/kg bolus 6 mg/kg bolus 0.8 mg/kg + 10 mg/kg/h 1 mg/kg + 15 mg/kg/h 3 mg/kg + 30 mg/kg/h 4 mg/kg + 40 mg/kg/h versus time, stratified for different
100 dosing regimens.
10
1
0.1

0 30 60 90120 0 30 60 90120 0 30 60 90120 0 30 60 90120 0 30 60 90120 0 30 60 90120

Time (min)

the final PK-BIS model, stratified for the 3 different dosing


regimens, is shown in Figure8. Plots of observed divided by
population-predicted concentrations over time are shown
in Figure9. MDPE and MDAPE are summarized in Table4.
Concentration (g/mL)

10
DISCUSSION
A recirculatory model, with 2 peripheral distribution com-
partments, a 5 tanks-in-series transit from venous to arte-
rial plasma, and 1 transit compartment from arterial to
venous plasma, adequately described the PK of AZD3043
in the healthy volunteers in the 2 studies. The elimination
of AZD3043 was fast, with an estimated plasma clearance
of AZD3043 of 2.2 L/min, which is >75% of the estimated
cardiac output (plasma flow) and greater than the antici-
1 pated liver blood flow, suggesting esterases not only in the
0 10 20 30 40 50 60
liver but also in blood to be involved in the metabolism.
Time (min) This finding is also supported by in vitro data.3 However,
no significant relationship between esterase activity and
Figure 4. Arterial (red) and venous (blue) concentrations for a typical
individual after a 30-minute infusion of 36 mg/kg/h. clearance was found in this analysis, which could have
been because of the limited range in esterase activity in
this healthy volunteer population, where normal esterase
Pharmacodynamics activity was an inclusion criterion for participation in the
The observations of BIS ranged from 4 to 98. A sigmoid study. Disease conditions or genetic polymorphism influ-
Emax model, where Emax was fixed to 1, i.e., a 100% decrease encing the esterase levels or coadministration of esterase
in BIS from baseline, described the relationship between inhibitors might still influence the clearance of AZD3043,
AZD3043 concentrations and BIS. EC50 was 15.6 g/mL, and caution should be taken when investigating such
with an interindividual variability of 37% (range, 4.138.3 patients or patients with unknown esterase activity. The
g/mL), and the Hill coefficient () was 1.7. No interindi- data did not support inclusion of sex or age on clearance,
vidual variability was estimated in . No significant effects but because the study was not designed to detect such dif-
(P > 0.1) of body weight, age, or sex on EC50 were found. ferences and the population was rather small and homog-
The rate constant for the effect delay, ke0, was 0.64/min enous, no firm conclusions could be made regarding a
(range, 0.04910.8), corresponding to a half-life of the effect broader population. An allometric model was the best
delay of 1.08 minutes (range, 0.06414.1). A 2-compart- descriptor of the relationship of body weight and clear-
ment effect-site model,16 with a distribution compartment ance parameters, whereas those for volumes were directly
off from the effect site, allowing for different onset and off- proportional to weight alone. In this homogenous popula-
set rates in relation to plasma concentrations, did not sig- tion, the difference between allometrically scaled param-
nificantly improve the fit (P > 0.1). Shrinkage was 15% eters and parameters directly proportional to body weight
in all PD parameters. The parameter estimates of the final is small, but the allometric model could be an advantage
PK-BIS model are presented in Table5. Key modeling steps when scaling to children or obese patients. However, fur-
are listed in Table2. Observed and predicted BIS, stratified ther studies in a wider range of body weights are needed
by dose group, are presented in Figure7. The PC-VPC for to draw any firm conclusions.

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Table 2.Key Modeling Steps in the Pharmacokinetic and Pharmacodynamic Analysis
Description Compared with Additional degrees of freedom OFV*
Pharmacokinetic model
Fifth compartment in the central circulation 4 compartments 0 14.4
Sixth compartment in the central circulation 5 compartments 0 18.1
Second compartment in the nondistributive pathway 1 compartment 0 22.5
Concentration-dependent VP1 Constant VP1 1 0.4
Concentration-dependent VP2 Constant VP2 1 4.0
Dose-dependent VP1 Constant VP1 1 17.9
Dose-dependent VP2 Constant VP2 1 28.7
VP1 dependent on accumulated dose Constant VP1 1 44.7
VP2 dependent on accumulated dose Constant VP2 1 21.6
VA dependent on accumulated dose Constant VA 1 52.2
Dose-dependent CL Constant CL 1 0.3
Parameters proportional to body weight No relation with body weight 0 41.7
Parameters allometrically scaled to body weight No relation with body weight 0 48.7
Pharmacodynamic model
Sigmoid Emax model Emax model 1 696.4
CL = plasma clearance; Emax = maximum effect; OFV = objective function value; VA = volume of arterial compartment; VP1 = volume of peripheral compartment 1;
VP2 = volume of peripheral compartment 2.
*P 0.05 for OFV 3.84 at 1 degrees of freedom; P 0.01 for OFV 6.64 at 1 degrees of freedom; P 0.001 for OFV 10.83 at 1 degrees of freedom.

Table 3.Parameter Estimates of the Final Recirculatory PK Model for AZD3043


Parameter Estimate (95% CI) IIV (95% CI) Description
CL (L/min) 2.20 (2.122.25) 14 (1216) Plasma elimination clearance
VA (L) 3.07 (2.343.96) 52 (3565) Volume of arterial compartment
Dose-VA (%/mg) 0.146 (0.1200.204) Effect of accumulated dose on VA
VV (L) 1.77 (1.142.13) 117 (95146) Volume of venous compartment
VC (L) 1.03 (0.681.44) 75 (6197) Volume of central circulation
VP1 (L) 1.56 (0.991.79) 97 (88113) Intercept for volume of peripheral compartment 1
Dose-VP1 (%/mg) 0.0252 (0.001300.0380) Effect of accumulated dose on VP1
VP2 (L) 7.21 (6.778.15) 29 (2132) Volume of peripheral compartment 2
Dose-VP2 (%/mg) 0.0338 (0.02400.0480) Effect of accumulated dose on VP2
QCO (L/min) 2.90 (2.503.20) 8.5 (414) Cardiac output (plasma flow)
QP1 (L/min) 1.41 (1.081.62) 24 (1932) Intercompartmental clearance 1
QP2 (L/min) 0.829 (0.7530.963) 29 (2133) Intercompartmental clearance 2
QND (L/min) 0.0235 (0.02040.0268) Intercompartmental clearance for nondistributive pathway
A,prop (%) 16.2 (14.417.9) Proportional residual variability for arterial concentrations
A,add (g/mL) 0.00287 (0.0007770.00391) Additive residual variability for arterial concentrations
V,prop (%) 25.4 (23.027.3) Proportional residual variability for venous concentrations
V,add (g/mL) 0.00432 (0.002510.00636) Additive residual variability for venous concentrations
All volumes and clearance terms refer to plasma where applicable. 95% CIs are obtained from a nonparametric bootstrap with sample size 1000. Parameter
estimates are for a typical individual of median weight (77 kg).
CL = plasma clearance; CI = confidence interval; IIV = interindividual variability expressed as percent coefficient of variation (%CV); PK = pharmacokinetic;
QCO = cardiac output (plasma flow); QND = plasma flow of nondistributive pathway; QP1 = plasma flow through peripheral compartment 1; QP2 = plasma flow through
peripheral compartment 2; VA = volume of arterial compartment; VV = venous volume; VC = volume of central circulation; VP1 = volume of peripheral compartment 1;
VP2 = volume of peripheral compartment 2.

The results from this analysis were consistent with the a large increase in apparent volume of distribution could
results from noncompartmental analyses performed in the have been because of lipids alone. Another hypothesis is
2 studies. A low but dose-dependent total apparent volume that cardiovascular effects could have influenced the dis-
of distribution, ranging from 15 L after the lowest dose tribution, because tachycardia was seen after greater doses.
to 37 L after the greatest dose in a typical individual was It is also possible that blood flows to different tissues are
estimated. The reason for dose-dependent distribution is altered during anesthesia, which could possibly alter the
unknown, but because AZD3043 is a lipophilic compound distribution.2224 The dose-dependent apparent volume of
administered as an emulsion, the distribution of the lipids distribution does not influence the area under the plasma
in the emulsion used in the drug formulation could poten- concentration-time curve or the steady-state concentrations,
tially influence the distribution of AZD3043. Similarly, infu- because they are dependent on clearance only, but the half-
sion of a lipid emulsion is used as treatment in situations of life is affected, meaning that the greater the dose, the lon-
overdoses of lipophilic local anesthetics19,20 where the local ger time it takes for the concentrations to decrease and for
anesthetics distribute to the infused lipids. a subject to recover after anesthesia. This could potentially
Litonius et al.21 showed that plasma concentrations be of importance if the apparent volume of distribution
of bupivacaine decreased and volume of distribution continues to increase after infusions >30 minutes studied.
increased when patients were treated with an IV lipid The maximum concentrations after a short infusion are also
emulsion. However, it could be questioned whether such influenced by the apparent volume of distribution, leading

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Recirculatory Pharmacokinetics and Pharmacodynamics of AZD3043

Figure 5. PRED-corrected visual predictive check for the arterial (top row) and venous (bottom row) concentrations versus time based on the
final pharmacokinetic model. Solid line is the PRED-corrected observed median, and the dashed lines are the 5th and 95th percentiles of
the PRED-corrected observations. The blue- and red-shaded areas represent the 95% confidence interval for the median and 5th and 95th
percentiles, respectively, of the simulated data (n = 1000). Left, 30-minute infusions; middle, bolus; right, bolus + 30-minute infusions. As
data were PRED corrected, all doses are shown on the same scale, and the PRED-corrected observations are not the same as the uncorrected
observations. PRED = population predictions.

10 10 10
DV/PRED (arterial)

DV/PRED (arterial)

DV/PRED (arterial)

1 1 1

0.1 0.1 0.1


0 30 60 90 120 150 0 30 60 90 120 150 0 30 60 90 120 150

Time (min) Time (min) Time (min)

10 10 10
DV/PRED (venous)

DV/PRED (venous)

DV/PRED (venous)

1 1 1

0.1 0.1 0.1


0 30 60 90 120 150 0 30 60 90 120 150 0 30 60 90 120 150

Time (min) Time (min) Time (min)


Figure 6. Observed divided by population-predicted concentrations over time. Top row, arterial concentrations; bottom row, venous concentra-
tions; left, 30-minute infusion; middle, bolus; right, bolus + 30-minute infusion.

to less than proportional increases in maximum concentra- of distribution of 91 L,16 compared with 2.2 L/min and 15
tions with increased dose. to 37 L for AZD3043. The high ke0 and the limited or rapid
The short terminal half-life, because of the high clear- distribution within the brain, as suggested by the lack of
ance and relatively low apparent volume of distribution, improvement of fit when applying a 2-compartment effect-
provides potential for a rapid recovery after anesthesia. In a site model, are consistent with a rapid onset and offset of
study with similar sampling, propofol was found to have a anesthesia. However, because of increasing volume of dis-
clearance of 1.6 L/min and a steady-state apparent volume tribution with greater doses, the terminal half-life could

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potentially be prolonged after long infusions. More stud-
Table 4.Median Prediction Error and Median
Absolute Performance Error of Observed Data in ies are needed to investigate whether this could affect the
Comparison with the Final Pharmacokinetic and recovery after long-term dosing.
Pharmacodynamic Models The recirculatory model contains a large number of
MDPE (%) MDAPE (%) parameters to obtain a physiologically plausible model.
Pharmacokinetic model The model has a tendency toward overparametrization,
Arterial concentrations 3.9 (21 to 30) 20 (10 to 37) resulting in the minimization easily ending up in local
Venous concentrations 1.7 (26 to 32) 26 (12 to 53) minima or not converging successfully. This is seen in the
Pharmacodynamic model log-likelihood profiling (Fig. 10), where the profiles are
BIS 0.75 (6.9 to 3.2) 3.9 (2.8 to 8.1)
not always smooth parabolas. However, simplifications of
Data are represented by median (1090 percentiles). the model would have the drawback of losing physiologic
BIS = bispectral index; MDPE = median prediction error; MDAPE = median
absolute performance error. interpretation.

Table 5.Parameter Estimates of the Final Pharmacodynamic Model for AZD3043


Parameter Estimate (95% CI) IIV (95% CI) Description
Baseline 93.9 (93.394.4) 3.3 (2.73.9) Baseline BIS
EC50 (g/mL) 15.6 (14.718.7) 37 (2745) Effect-site concentration needed to reach 50% of Emax
1.7 (1.531.89) Shape factor
ke0 (per min) 0.640 (0.5530.834) 91 (67114) Rate constant for delay of effect
4.93 (4.665.20) Additive residual variability
95% CIs are obtained from a nonparametric bootstrap with a sample size of 1000.
BIS = bispectral index; CI = confidence interval; IIV = interindividual variability expressed as percent coefficient of variation (%CV).

1 mg/kg/h 3 mg/kg/h 6 mg/kg/h 12 mg/kg/h 18 mg/kg/h 27 mg/kg/h


100
80
60
40
20
0 36 mg/kg/h 54 mg/kg/h 81 mg/kg/h 1 mg/kg bolus 1.5 mg/kg bolus 2 mg/kg bolus
100
80
60
BIS

Figure 7. Individual observed (blue)


40 and typical predicted (red) BIS versus
20 time, stratified for different dosing
0 4 mg/kg bolus 6 mg/kg bolus 0.8 mg/kg + 10 mg/kg/h 1 mg/kg + 15 mg/kg/h 3 mg/kg + 30 mg/kg/h 4 mg/kg + 40 mg/kg/h regimens. BIS = bispectral index.
100
80
60
40
20
0
0 20 40 60 0 20 40 60 0 20 40 60 0 20 40 60 0 20 40 60 0 20 40 60

Time (min)

Figure 8. PRED-corrected visual predictive check for the BIS model. Solid black line is the PRED-corrected median, and the dashed black lines
are the 5th and 95th percentiles of the PRED-corrected observations. The blue- and red-shaded areas represent the 95% confidence interval
for the median and 5th and 95th percentiles, respectively, of the simulated data (n = 1000). Left, 30-minute infusions; middle, bolus; right,
bolus + 30-minute infusions. As data were PRED corrected, all doses are shown on the same scale, and the PRED-corrected observations are
not the same as the uncorrected observations. BIS = bispectral index; PRED = population predictions.

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Recirculatory Pharmacokinetics and Pharmacodynamics of AZD3043

40 40 40

DVPRED (BIS)

DVPRED (BIS)

DVPRED (BIS)
20 20 20

0 0 0

20 20 20

40 40 40
0 30 60 0 30 60 0 30 60

Time (min) Time (min) Time (min)


Figure 9. Observed dependent variable (DV) minus population-predicted (PRED) BIS over time. Left, 30-minute infusion; middle, bolus; right,
bolus + 30-minute infusion. BIS = bispectral index.

CL QP1 QP2 QCO QND

6 6 6 6 6
dOFV

dOFV

dOFV

dOFV

dOFV
4 4 4 4 4

2 2 2 2 2

0 0 0 0 0
2.102.152.202.252.30 1.1 1.2 1.3 1.4 1.5 0.75 0.85 0.95 2.62.72.82.93.03.1 0.020 0.024

Estimate Estimate Estimate Estimate Estimate

VA VV VP1 VP2 VC

6 6 6 6 6
dOFV

dOFV

dOFV

dOFV

dOFV
4 4 4 4 4

2 2 2 2 2

0 0 0 0 0
2.5 3.0 3.5 4.0 1.0 1.5 2.0 1.0 1.2 1.4 1.6 1.8 6.5 7.0 7.5 8.0 0.15 0.20 0.25

Estimate Estimate Estimate Estimate Estimate

DoseVA DoseVP1 DoseVP2

6 6 6
dOFV

dOFV

dOFV

4 4 4

2 2 2

0 0 0
0.00100.00140.0018 0e+00 3e04 6e04 1e04 4e04 7e04

Estimate Estimate Estimate

Figure 10. Log-likelihood profiles of the pharmacokinetic parameters. CL = elimination clearance; Dose-VA, Dose-VP1, and Dose-VP2 = effect
of accumulated dose on VA, VP1, and VP2, respectively; QCO = cardiac output (plasma flow); QND = plasma flow of nondistributive pathway;
QP1 = plasma flow through peripheral compartment 1; QP2 = plasma flow through peripheral compartment 2; VA = arterial volume; VV = venous
volume; VC = volume of central circulation; VP1 = volume of peripheral compartment 1; VP2 = volume of peripheral compartment 2.

The large range of ke0 was because of a few outlying sub- titration, which is commonly used in anesthesia practice. In
jects with very high or low values. The subjects with the 2 subjects in the greatest dose group, sudden and transient
lowest ke0 (longest equilibration time) received low doses increases in BIS were seen during the infusion, despite the
with a small effect on BIS, and it is possible that lying still subjects being deeply anesthetized as judged by the inves-
in a quiet room also could have influenced BIS in these sub- tigators. The reason for this is unknown, but could possi-
jects. was estimated to be 1.7, implying a steeper concen- bly be because of other electroencephalogram signals that
trationeffect relationship than for an Emax model. The is in distort the transformation into BIS. One subject receiving
line with what was found for propofol in a similar setting.16 the greatest dose had a large outlying decrease in BIS from
The PK and PD properties of AZD3043, with its fast onset approximately 15 to 30 minutes after start of infusion. The
and offset of effect, suggest it may be suitable for individual reason for this is unknown.

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In conclusion, a recirculatory model, with 2 peripheral 5. Norberg A, Koch P, Kanes SJ, Bjrnsson MA, Barassin S, Ahlen
distribution compartments, a 5 tanks-in-series transit delay K, Kalman S. A bolus and bolus followed by infusion study of
AZD3043, an investigational intravenous drug for sedation and
from venous to arterial plasma, and a single compartment anesthesia: safety and pharmacodynamics in healthy male and
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DISCLOSURES ity of the observers assessment of alertness/sedation scale:
study with intravenous midazolam. J Clin Psychopharmacol
Name: Marcus A. Bjrnsson, MSc Pharm, PhD.
1990;10:24451
Contribution: This author helped design the studies, analyze 10. Beal S, Sheiner LB, Boeckmann A, Bauer RJ, eds. NONMEM
the data, and write the manuscript. Users Guides (19892009). Ellicott City: ICON Development
Attestation: Marcus A. Bjrnsson has seen the original study Solutions, 2009
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manuscript. of computer intensive statistical methods for non-linear mixed
effect modeling using NONMEM. Comput Methods Programs
Conflicts of Interest: Marcus A. Bjrnsson was employed by
Biomed 2005;79:24157
AstraZeneca and has equity interest in AstraZeneca. 12. Jonsson EN, Karlsson MO. Xposean S-PLUS based popu-
Name: ke Norberg, MD, PhD. lation pharmacokinetic/pharmacodynamic model build-
Contribution: This author helped design the studies, conduct ing aid for NONMEM. Comput Methods Programs Biomed
the studies, analyze the data, and write the manuscript. 1999;58:5164
Attestation: ke Norberg has seen the original study data, 13. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-
corrected visual predictive checks for diagnosing nonlinear
reviewed the analysis of the data, and approved the final mixed-effects models. AAPS J 2011;13:14351
manuscript. 14. Varvel JR, Donoho DL, Shafer SL. Measuring the predic-

Conflicts of Interest: ke Norberg received an honorarium tive performance of computer-controlled infusion pumps.
from AstraZeneca 3 years ago for participating in an advisory J Pharmacokinet Biopharm 1992;20:6394
board on AZD3043. 15. Holford NH. A size standard for pharmacokinetics. Clin

Name: Sigridur Kalman, MD, PhD. Pharmacokinet 1996;30:32932
16. Zhang L, Beal SL, Sheiner LB. Simultaneous vs. sequential

Contribution: This author helped design the studies, conduct analysis for population PK/PD data I: best-case performance.
the studies, analyze the data, and write the manuscript. J Pharmacokinet Pharmacodyn 2003;30:387404
Attestation: Sigridur Kalman approved the final manuscript. 17. Bjrnsson MA, Norberg A, Kalman S, Karlsson MO, Simonsson
Conflicts of Interest: Sigridur Kalman received an honorarium US. A two-compartment effect site model describes the
from AstraZeneca 3 years ago for participating in an advisory bispectral index after different rates of propofol infusion.
J Pharmacokinet Pharmacodyn 2010;37:24355
board on AZD3043.
18. Savic RM, Karlsson MO. Importance of shrinkage in empirical
Name: Ulrika S. H. Simonsson, MSc Pharm, PhD. Bayes estimates for diagnostics: problems and solutions. AAPS
Contribution: This author helped analyze the data and write J 2009;11:55869
the manuscript. 19. Ciechanowicz S, Patil V. Lipid emulsion for local anesthetic sys-
Attestation: Ulrika S. H. Simonsson approved the final manuscript. temic toxicity. Anesthesiol Res Pract 2012;2012:131784
Conflicts of Interest: Ulrika S. H. Simonsson has equity interest 20. Weinberg GL. Lipid emulsion infusion: resuscitation for

local anesthetic and other drug overdose. Anesthesiology
in AstraZeneca. 2012;117:1807
This manuscript was handled by: Steven L. Shafer, MD. 21. Litonius E, Tarkkila P, Neuvonen PJ, Rosenberg PH. Effect of
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