Clin Pharmacokinet
https://doi.org/10.1007/s40262-018-0629-6
ORIGINAL RESEARCH ARTICLE
Population Pharmacokinetics of Elagolix in Healthy Women
and Women with Endometriosis
Insa Winzenborg1 • Ahmed Nader1 • Akshanth R. Polepally1 •
Mohan Liu1 • Jacob Degner1 • Cheri E. Klein1 • Nael M. Mostafa1 •
Peter Noertersheuser1 • Juki Ng1
Springer International Publishing AG, part of Springer Nature 2018
Abstract
Introduction Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH)
receptor antagonist in development for the management of
endometriosis with associated pain and heavy menstrual
bleeding due to uterine fibroids. The pharmacokinetics of
elagolix have been well-characterized in phase I studies;
however, elagolix population pharmacokinetics have not
been previously reported. Therefore, a robust model was
developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters.
Methods The data from nine clinical studies (a total of
1624 women) were included in the analysis: five phase I
studies in healthy, premenopausal women and four phase
III studies in premenopausal women with endometriosis.
Results Elagolix population pharmacokinetics were best
described by a two-compartment model with a lag time in
absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting
polypeptide (OATP) 1B1 genotype status, had a
Insa Winzenborg and Ahmed Nader contributed equally to the
pharmacokinetic model design and execution as well as to the writing
of this manuscript.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s40262-018-0629-6) contains supplementary material, which is available to authorized users.
& Ahmed Nader
ahmed.nader@abbvie.com
1
Clinical Pharmacology and Pharmacometrics, Department
R4PK, AbbVie Inc., Building AP31-3, 1 North Waukegan
Road, North Chicago, IL 60064, USA
statistically significant, but not clinically meaningful, effect
on elagolix CL/F.
Conclusion Elagolix pharmacokinetics were not affected
by patient demographics and were similar between healthy
women and women with endometriosis.
Clinical Trial Registration Numbers NCT01403038,
NCT01620528,
NCT01760954,
NCT01931670,
NCT02143713.
Key Points
Elagolix population pharmacokinetics in 313 healthy
women and 1311 women with endometriosis were
best described by a two-compartment model with a
lag time in absorption.
Organic anion transporting polypeptide (OATP) 1B1
genotype status was the only covariate affecting
elagolix apparent clearance, but did not result in
clinically meaningful changes in elagolix plasma
exposure.
Elagolix pharmacokinetics were similar between
healthy women and women with endometriosis.
1 Introduction
Endometriosis, which affects approximately 6–10% of
women of reproductive age [2], is characterized by the
presence of endometrial-like tissue outside the uterus,
which provokes a chronic, inflammatory condition [1].
I. Winzenborg et al.
Endometriosis primarily affects women of childbearing age
and is frequently associated with a range of symptoms
including dysmenorrhea, non-menstrual pelvic pain, as
well as dyspareunia [3]. Current first-line therapies for
endometriosis-related pain include pain relievers (nonsteroidal anti-inflammatory drugs [NSAIDs]) and oral contraceptives. Second-line therapies involve injectable depot
formulations of gonadotropin-releasing hormone (GnRH)
agonists, such as leuprolide acetate. Medical treatment
options remain limited and there is a significant unmet
medical need for non-surgical treatments.
Elagolix is a novel, orally active, non-peptide, competitive GnRH receptor antagonist in development for the
management of endometriosis with associated pain and
heavy menstrual bleeding due to uterine fibroids. Elagolix
offers patients many benefits as it has a rapid onset of
action, is orally bioavailable, does not produce a flare
effect, and can be readily discontinued if necessary [4, 5].
In addition, elagolix has the ability to reduce gonadotropins
(luteinizing hormone [LH], and follicle-stimulating hormone [FSH]) and ovarian (estradiol) hormones in a dosedependent manner, raising the possibility of tailoring the
dose to achieve an acceptable balance between therapeutic
efficacy and unwanted adverse effects [6]. Data from phase
II and phase III trials have demonstrated efficacy and safety
of elagolix as a therapy for endometriosis with associated
pain [7–9].
The pharmacokinetic profile of elagolix has been wellcharacterized in a number of phase I studies. Following
oral dosing, elagolix is rapidly absorbed reaching maximum concentrations at 1.0–1.5 h with a half-life of 4–6 h
[6]. Elagolix doses of 150 mg once daily or 200 mg twice
daily were tested in phase III studies for the treatment of
endometriosis with associated pain.
Elagolix population pharmacokinetics have not been
previously reported. The elagolix clinical development
program has yielded the largest dataset in women with
endometriosis, allowing for development of a robust population pharmacokinetic model. The aim of this analysis
was to develop a model to describe elagolix population
pharmacokinetics and to evaluate factors affecting elagolix
exposures in order to better assess key elagolix efficacy and
safety outcomes measures.
2 Methods
2.1 Clinical Studies Included in the Analysis
The data from nine clinical studies (five phase I and four
phase III studies) were included in this population pharmacokinetic analysis. The phase I studies enrolled healthy,
premenopausal women and the phase III studies enrolled
premenopausal
women
with
moderate-to-severe
endometriosis-associated pain. Study design information
for the phase I studies and treatment regimens for all nine
studies are described in Table 1. Subjects in the phase I
studies had a history of regular menstrual cycles, with a
duration of 24–32 days with at least 3 and no more than
7 days of bleeding per month for a minimum of 3 months
prior to study drug administration. Study design information for the phase 3 studies, including inclusion and
exclusion criteria, was previously reported [8].
Elagolix dosing regimens for the studies in this analysis
included single doses of 150 or 200 mg and multiple doses
ranging from 100 mg once daily to 400 mg twice daily;
dosing duration for multiple doses ranged from 21 days to
12 months [6, 8, 10–12].
All study participants provided written informed consent. Study protocols were approved by the institutional
review boards or ethics committees, and study procedures
were conducted in accordance with International Council
for Harmonization Good Clinical Practice guidelines and
ethical principles that have their origin in the Declaration
of Helsinki.
2.2 Study Drug Dosing and Pharmacokinetic
Sampling
For Studies 1, 2, 3 and 4 (Table 1), doses were administered on-site; therefore, dosing times were based on
observed study drug administration. Doses for Study 5
were self-administered by the study subjects and dosing
times for that study were based on daily diaries obtained
from individual subjects. The phase III studies (women
with endometriosis) employed electronic compliance
packaging to dispense study drug to study patients. Each
patient received a monthly kit which contained weekly
blister packs for dosing. Patients returned the compliance
kits during their monthly visits; the kits were sent to
Information Mediary Corporation (IMC, Ottawa, ON,
Canada) where they were scanned to generate study- and
patient-specific compliance reports. This method provided
a detailed profile of patients’ dosing behavior and exact
dosing times for the majority of doses in the population
pharmacokinetic analysis.
Blood sample collection times varied according to the
protocol specifications for each study; sampling times are
detailed in Table 1. The actual blood sample collection
times were used for the population pharmacokinetic
analysis.
2.3 Bioanalysis
Blood samples for assay of elagolix were collected in K2ethylenediaminetetraacetic
acid
(EDTA)-containing
Study
(Clinicaltrials.gov
identifier)
Study site
N
IRB
Study design
Elagolix treatment
Pharmacokinetic sampling times
Bioanalysis
informationa
Duration
Regimen
150 mg qd,
100 mg bid,
200 mg bid,
300 mg bid,
or 400 mg
bid
Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10,
12, 16, and 24 h after dosing; prior
to dosing on Days 5, 7, 9, 15, 17,
and 19; day 21: 0, 0.5, 1, 1.5, 2, 3,
4, 6, 8, 10, 12, 16, 24, 36 and 48 h
after dosing
Precision: B 11.4%
0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8,
10, 12, 16, and 24 h after dosing in
each period
Precision: B 2.3%
Phase I studies (healthy, premenopausal women)
Study 1 [6]
Study 2
Study 3
Study 4
Study 5
(NCT01403038)
[10–12]
34
23
23
54
179
ACPRU,
Waukegan, IL,
USA
Vista Health
System,
Waukegan,
IL, USA
Randomized, placebo-controlled,
MAD, double-blind study to
evaluate safety and PKs/PDs in
healthy women
21 days
ACPRU,
Waukegan, IL,
USA
Vista Health
System,
Waukegan,
IL, USA
Randomized, open-label, singledose, crossover study to
evaluate safety and PKs in
healthy women
Single
doses
150 mg
ACPRU,
Grayslake, IL,
USA
Vista Health
System,
Waukegan,
IL, USA
Randomized, open-label, singledose, crossover study to
evaluate safety and PKs in
healthy women
Single
doses
200 mg
PPD
Development,
LP, Austin,
TX, USA
Salus IRB,
Austin, TX,
USA
Randomized, open-label, singledose, crossover study to
evaluate safety and PKs in
healthy women
Single
doses
20 sites in the
USA
7 IRBs
provided
protocol
review and
approval
Open-label, multiple-dose study
to evaluate safety and PDs in
healthy women
3 cycles
(84 days)
Accuracy: - 6.9 to
7.2%
LLOQ: 0.126 ng/
mL
Accuracy: - 3.8 to
2%
LLOQ: 1.57 ng/mL
2 9 100 mg
0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8,
10, 12, 16, and 24 h after dosing in
each period
Precision: B 11.3%
Accuracy: - 1.6 to
8.5%
LLOQ: 0.115 ng/
mL
2 9 100 mg
0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8,
10, 12, 16, 24, 30, and 36 h after
dosing in each period
Precision: B 8.1%
Accuracy: - 3.6 to
4.7%
LLOQ: 0.102 ng/
mL
100 mg qd,
150 mg qd,
200 mg qd,
100 mg bid,
200 mg bid,
300 mg bid
One sample on Weeks 2 and 4 of
Cycles 1, 2, and 3 during clinic
visit
Precision: B 12.3%
Accuracy: - 2.4 to
7.4%
LLOQ: 0.126 ng/
mL
Elagolix Population Pharmacokinetics
Table 1 Studies included in the population pharmacokinetic model
Table 1 continued
Study
(Clinicaltrials.gov
identifier)
N
Study site
IRB
Study design
Elagolix treatment
Duration
Regimen
6 months
150 mg qd or
200 mg bid
Pharmacokinetic sampling times
Bioanalysis
informationa
Day 1 (approximately 1 h after
dosing, for pivotal studies only)
and at Months 1, 2, 3, 4, 5, and 6
(or D/C) clinic visits
Precision: B 374%
Phase III studies (premenopausal women with moderate-to-severe endometriosis-associated pain)
Elaris EM-I
(NCT01620528)
[8]
Elaris EM-I-ext
(NCT01760954)
[8]
1311
Pivotal studies with extensions
Multicenter, double-blind,
randomized, placebo-controlled,
phase III trials of 6-month
treatment with elagolix in
women with moderate or severe
endometriosis-associated pain
Accuracy: - 7.3 to
5.8%
LLOQ: 0.102 ng/
mL
Precision: B 124%
Accuracy: - 3.7 to
25%
LLOQ: 0.102 ng/
mL
Elaris EM-II
(NCT01931670)
[8]
Elaris EM-II-ext
(NCT02143713)
[8]
Precision: B 8.3%
Accuracy: - 3.1 to
4.9%
LLOQ: 0.102 ng/
mL
Precision: B 9.0%
Accuracy:
0.6–2.6%
LLOQ: 0.995 ng/
mL
ACPRU AbbVie Clinical Pharmacology Research Unit, bid twice daily, D/C premature discontinuation, IRB institutional review board, LLOQ lower limit of quantification, MAD multipleascending dose, N number of volunteers included in the population pharmacokinetic analysis, PD pharmacodynamic, PK pharmacokinetic, qd once daily
a
Precision is expressed as % coefficient of variation (%CV); accuracy is expressed as percentage bias
I. Winzenborg et al.
Elagolix Population Pharmacokinetics
collection tubes. Sufficient blood was collected to provide
1.5–3 mL plasma from each sample. Immediately after
collection, the blood samples were inverted several times
to ensure good mixing of the blood and anticoagulant;
samples were then placed in an ice bath. The blood samples
for elagolix assay were centrifuged (1100–1600 rpm for
10 min) using a refrigerated centrifuge to separate the
plasma within 2 h of collection. The plasma samples were
transferred using plastic pipettes into labeled, screw-capped polypropylene tubes. The plasma samples were placed
in the freezer within 2 h after collection and maintained at
- 20 C or colder until shipped to the sponsor. The frozen
plasma samples for elagolix assay were packed in dry ice
sufficient to last during transport to the sponsor for analysis. The samples were processed and assayed using a
validated salt-assisted protein precipitation extraction,
high-performance liquid chromatography–tandem mass
spectrometric (LC–MS/MS) method similar to the methods
previously published (AbbVie Bioanalysis Lab, North
Chicago, IL, USA) [6, 13]. Samples were analyzed by
subject. The precision (coefficient of variation) for elagolix
plasma concentration determination was B 11.4% and
accuracy (expressed as percentage bias) ranged from - 6.6
to 7.2%. The lower limits of quantitation were between 0.1
and 1.0 ng/mL for the phase I studies and were approximately 0.1 ng/mL for the phase III studies. Precision,
accuracy, and the lower limit of quantification (LLOQ) for
each study are provided in Table 1.
2.4 Pharmacogenetic Testing
Deoxyribonucleic acid was isolated from whole blood
samples using Qiagen reagent kits (Qiagen Inc., Valencia,
CA, USA) applied to an AutoGenprep 3000 automated
DNA extraction instrument. Genotypes were determined
for the following nucleotide polymorphisms in OATP1B1
for rs4149056 [14]. All genotypes were determined using
the pyrosequencing detection method (Qiagen Inc.,
Valencia, CA, USA). SLCO1B1 genetic variant
521T[C(S5) genotype was assayed to classify subjects into
one of three different OATP1B1 transporter status categories, extensive transporter (ET); intermediate transporter
(IT); or poor transporter (PT), based on the following
criteria:
•
•
•
Homozygous variant 521T[C(s5) ? PT
Heterozygous for 521T[C(s5) ? IT
Homozygous wild-type 521T[C(s5) ? ET.
2.5 Population Pharmacokinetic Model
Development
Population pharmacokinetic models were built using nonlinear mixed-effects modeling in NONMEM 7.3 (ICON
Development Solutions, Hanover, MD, USA). Model
building was conducted using the first-order conditional
estimation method with g–e interaction (FOCEI) within
NONMEM and included development of the appropriate
structural model, models for inter-individual variability
(IIV) and residual error, and the testing of potential
covariate–parameter relationships. One-, two-, and threecompartment pharmacokinetic models with first-order
absorption (with or without lag time for absorption) and
elimination were evaluated and the model that best
described the observed concentration–time data was
selected. Covariate selection was conducted using forward
inclusion and backward elimination procedures to identify
statistically significant covariate–parameter relationships.
Several criteria were used to evaluate improvement in
model performance and to select the final model. The
likelihood ratio test was used to discriminate among
alternative nested models using the difference in objective
function values (OFV) provided by NONMEM (p\0.01
for forward inclusion and p\0.001 for backward elimination in covariate testing).
Model development was guided by goodness-of-fit
plots, likelihood ratio tests, physiologic plausibility, and
precision of parameter estimates, as well as previous
knowledge of elagolix pharmacokinetics. The covariates
investigated for influence on elagolix apparent clearance
(CL/F) and apparent volume of central compartment distribution (Vc/F) included age, body weight, body mass
index (BMI), race, ethnicity, albumin, bilirubin, aspartate
aminotransferase (AST), alanine aminotransferase (ALT),
tobacco use, alcohol use, organic anion transporting
polypeptide (OATP) 1B1 genotype status, and study region
(subjects in the USA versus those outside the USA). Serum
creatinine and creatinine clearance (estimated using
Cockcroft–Gault equation) were also tested for effect on
CL/F. OATP1B1 genotype status was determined since
elagolix is a substrate of OATP1B1 and, thus, its elimination through hepatic metabolism may be dependent on
OATP1B1-mediated hepatic uptake [15].
Continuous covariates were entered in the model using
either a power (Eq. 1) or a multiplicative function (Eq. 2),
normalized or centered around the median value as shown
in the following example equations:
I. Winzenborg et al.
h2
WTKGi
;
TVCLi ¼ h1
median WTKG
ð1Þ
TVCLi ¼ h1 ð1 þ h2 ðALBi
ð2Þ
median ALBÞÞ;
where TVCLi is the typical value of elagolix CL/F for
individual patient i, h1 is the typical value of CL/F for an
individual with a median weight (WTKG) in Eq. 1, and an
individual with a median baseline albumin (ALB) level in
Eq. 2, and h2 is the covariate effect constant relating the
fixed effect (e.g., WTKGi and ALBi) to the elagolix CL/F.
Dichotomous covariates were entered in the model via a
binary indicator variable in a multiplicative way. For
example (Eq. 3):
TVCLi ¼ h1 ð1 þ h2 ÞETHi ;
ð3Þ
where TVCLi is the typical value of elagolix CL/F for
individual i, and ETHi is the individual’s covariate value
(coded as either 0 or 1), such that if ETHi = 0 then
TVCLi = h1 and if ETHi = 1 then TVCLi = h1(1 ? h2).
IIV was modeled using an exponential error model and
residual variability was modeled using a combined additive
and proportional error model.
The final model individual parameter estimates and
daily dosing records were used to estimate daily concentration–time profiles and to calculate individual elagolix
pharmacokinetic exposures. Steady-state functionality was
used for modeling in the case of missing dosing times, i.e.,
if kits were not returned, could not be read, or if patients
extracted multiple doses from the kit at the same time.
Missing dosing times for Study 5 were imputed based on
the last valid dosing information.
Since intensive pharmacokinetic sampling and closely
monitored dosing times were not feasible in phase I Study
5 and the phase III studies, rules for outlier exclusion for
the sparse data were created for the pharmacokinetic
analysis based on concentrations observed in the phase I
studies with intensive sampling. A data exclusion rule was
developed using the distribution of intensive pharmacokinetic concentration–time profiles from 134 women in
Studies 1–4 (phase I) and was used to remove highly
unlikely measurements collected from studies with sparse
sampling (Study 5 and the phase III studies).
An analysis of variance (ANOVA) was used on data
from the phase I studies with intensive sampling to identify
variance that can be explained by time after last dose
(TALD) and administered dose. The residual error of the
ANOVA model was used to describe the deviations from
the mean for each TALD and dose. The standard deviation
of the residual error was then quantified by the root mean
squared error (RMSE). This analysis used the log10-transformed observed concentrations, hence the residuals were
approximately normally distributed (99.7% of data expected to be within a three-fold RMSE around the mean). A
more conservative exclusion range of four-fold RMSE was
considered as the plausible interval for determination of
outlier data for Study 5 as well as phase III studies. Furthermore, a seven-fold RMSE around the mean was used
for the initial absorption phase (until 0.75 h after last dose)
in order to avoid exclusion of too many samples in the
steep incline phase, where values outside the four-fold
RMSE are more likely to occur if small deviations in
individual subject absorption rates exist. Elagolix concentrations outside these intervals were classified as outlying
measurements. Additional information regarding the data
exclusion rule is provided in the Electronic Supplementary
Material.
2.6 Model Evaluation
Model evaluation included diagnostic goodness-of-fit plots,
visual predictive checks (VPCs), and bootstrap evaluation.
For VPCs, final model parameters were used to simulate
500 replicates of the predictions using the NONMEM
$SIMULATION option. VPCs of the concentration–time
profile were then created by superimposing the individual
observed concentrations over relevant percentiles (median,
5th, and 95th) of the simulations. 95% prediction intervals
around each of the simulation percentiles were also included to demonstrate variability in simulated concentrations.
For phase I VPCs, a prediction-correction was performed
since several dosing regimens are presented, as described
by Bergstrand et al. [16].
Furthermore, in order to estimate confidence intervals of
the model parameters, 1000 bootstrap replicates were
constructed by randomly sampling N patients with
replacement from the original dataset, where N is the
number of patients in the original dataset. Model parameters from the bootstrap replicates that had successfully
converged were summarized to yield medians and 2.5th
and 97.5th percentiles. Final model parameters based on
the original dataset were compared against the bootstrap
results.
3 Results
The population pharmacokinetic analysis was based on
concentrations derived from 1624 women enrolled in five
phase I and four phase III studies. A summary of the
demographic characteristics for volunteers included in the
analysis is presented in Table 2.
Elagolix Population Pharmacokinetics
Table 2 Baseline
demographics and
characteristics
All study volunteers (N = 1624)a
Demographic characteristic (units)
Age (years)
32 (18–49)
Body weight (kg)
74 (40–148)
Body mass index (kg/m2)
27 (16–56)
Serum creatinine (mg/dL)
0.7 (0.4–1.3)
Creatinine clearance (mL/min)
133.3 (53.6–346.8)
Aspartate aminotransferase (IU/L)
18.8 (9.0–275.0)
Alanine aminotransferase (IU/L)
15.9 (4.0–367.0)
Albumin (g/dL)
4.5 (3.6–5.4)
Total bilirubin (mg/dL)
0.5 (0.1–1.9)
Race
Black
194 (12)
White and others
1430 (88)
Geographic region
USA
1287 (79)
Outside the USA
OATP1B1 genotype status
337 (21)
Extensive transporter (ET)
858 (53)
Intermediate transporter (IT)
279 (17)
Poor transporter (PT)
30 (2)
Unknowna
457 (28)
Values are given as mean (range) or n (%)
OATP1B1 organic anion-transporting polypeptide 1B1
a
For some volunteers, no pharmacogenetic sample was available for analysis
3.1 Data Disposition and Exclusions
The population pharmacokinetic analysis included a total
of 3655 plasma concentrations from 313 healthy, premenopausal women in phase I studies and a total of 8637
plasma concentrations from 1311 premenopausal women
with endometriosis in phase III studies (including women
who switched from placebo in the pivotal studies to elagolix treatment in the extension studies). For Studies 1–4
(phase I studies with intensive sampling), all available
pharmacokinetic data were used in the calculation of the
pharmacokinetic parameters; therefore, all subjects were
included in the pharmacokinetic analysis. For Study 5
(phase I study with sparse sampling), seven subjects were
excluded from the pharmacokinetic analysis because they
had no measurable elagolix plasma concentrations above
the LLOQ at any visit. For the phase III studies (sparse
sampling), 127 patients were excluded due to missing
sample times or incorrect sample identifiers and 72 patients
were excluded because they did not have any measurable
elagolix plasma concentrations above the LLOQ. Data
below the LLOQ were imputed for the population pharmacokinetic analysis, as follows: the first individual plasma
concentration below the LLOQ following the study drug
administration was set to one-half the LLOQ (LLOQ/2); all
subsequent observations below the LLOQ for that subject
after the same dose were excluded from the analyses.
A data exclusion rule was developed and was used to
remove implausible measurements collected from studies
with sparse sampling (Study 5 and the phase III studies)
from further analysis. All available elagolix concentrations
from the studies with sparse sampling were included in the
population pharmacokinetic analysis, with the exception of
samples that fulfilled at least one of the five criteria from
the data exclusion rule (criteria are presented in the Electronic Supplementary Material). No phase I intensive
pharmacokinetic data were excluded based on this data
exclusion rule. In total, pharmacokinetic concentrations
from 24 patients from Elaris Endometriosis (EM)-I and 41
patients from Elaris EM-II were completely excluded from
the pharmacokinetic model development because all their
concentration measurements were below the limit of
quantification (BLQ). Two patients in Elaris EM-I and one
patient in Elaris EM-II that had at least two non-BLQ
pharmacokinetic samples less than 48 h after last dose
were completely excluded from the pharmacokinetic
analysis due to the data exclusion rule. Additional information regarding the data exclusion rule is provided in the
Electronic Supplementary Material.
I. Winzenborg et al.
Table 3 Parameter estimates and covariate effects for elagolix based on final population pharmacokinetic model and bootstrap evaluation
Parameter
Final pharmacokinetic model
Population estimate (SEE)
Bootstrap evaluation
% RSE
a
Median
2.5th and 97.5th percentiles
Pharmacokinetic parameters
CL/F (L/h)
118 (1.54)
1.30
118
(114, 121)
Vc/F (L)
257 (4.46)
1.74
257
(246, 270)
ka (1/h)
2.49 (0.076)
3.04
2.50
(2.21, 2.83)
Q/F (L/h)
5.83 (0.247)
4.23
5.83
(4.46, 7.00)
Vp/F (L)
Lag-time (h)
OATP1B1 = IT/PT on CL/F
59.6 (1.56)
2.62
0.202 (0.002)
- 0.142 (0.020)
0.925
- 13.7
59.8
(53.5, 68.5)
0.203
- 0.142
(0.192, 0.215)
(- 0.182, - 0.102)
IIV and residual variability
IIV on CL/F (%CV)b
0.166 (42.5)
5.12
0.167
(0.147, 0.191)
IIV on Vc/F (%CV)b
0.231 (51.0)
6.36
0.233
(0.194, 0.279)
Covariance of IIV on CL/F and Vc/F
0.133 (37.7)
7.18
IIV on residual error (% CV)b
0.131 (37.4)
6.46
0.128
(0.084, 0.166)
Proportional error
0.228 (0.006)
Additive error
0.149 (0.016)
2.79
10.6
0.228
(0.215, 0.240)
0.143
(0.072, 0.251)
CL/F apparent clearance, IIV inter-individual variability, IT/PT intermediate transporter/poor transporter, ka first-order absorption rate constant,
OATP1B1 organic anion-transporting polypeptide 1B1, Q/F apparent inter-compartmental clearance, SEE standard error of estimate, Vc/F
apparent volume of central compartment distribution, Vp/F apparent volume of distribution in the peripheral compartment, % CV percentage
coefficient of variation, % RSE percentage relative standard error
a
% RSE was estimated as: SEE/population estimate 9 100
b
% CV = SQRT(exp(ETA) - 1) 9 100
3.2 Population Pharmacokinetic Model Results
A two-compartment model with a lag-time in absorption,
IIV on CL/F and Vc/F, and a combined residual error best
described elagolix pharmacokinetics (Table 3). The IIV on
residual error [ETA(3)] was introduced in order to account
for individual differences in the accuracy of dosing or
pharmacokinetic sampling times (Eq. 4):
Y ¼ IPRED ð1 þ EPSð1Þ EXPðETAð3ÞÞÞ
þ EPSð2Þ EXPðETAð3ÞÞ;
ð4Þ
where IPRED is the individual-predicted concentration,
EPS(1) is the proportional error term, and EPS(2) is the
additive error term.
The only covariate lowering the OFV significantly (44
units) was OATP1B1 genotype as a covariate on CL/
F (Fig. 1). Women with genotype status of IT or PT had
14% lower CL/F than those with ET (extended transporter)
genotype status for OATP1B1. The addition of OATP1B1
as a covariate on elagolix CL/F resulted in a minor
decrease in IIV on elagolix CL/F from 43.9 to 42.5%. None
of the other covariates, including body weight and BMI,
were significant in the final population pharmacokinetic
model (Table 3). Evaluation of the relationship of post hoc
CL/F and Vc/F estimates against healthy subjects or
patients with endometriosis showed no clear trend for
differences in pharmacokinetic parameters between the two
populations (Fig. 2). Accordingly, elagolix pharmacokinetics was considered similar between healthy subjects and
patients with endometriosis.
Predicted elagolix exposures using the final pharmacokinetic model were determined for the 150 mg oncedaily and 200 mg twice-daily dosing regimens. The median
(5–95% percentiles) predicted average plasma concentration (Cavg) and area under the plasma concentration–time
curve from time zero to 24 h (AUC24) values were 43.6
(14.2–99.9) ng/mL and 1050 (340–2400) ngh/mL,
respectively, for the 150 mg once-daily dosing regimen
and were 120 (38.2–262) ng/mL and 2890 (916–6300)
ngh/mL, respectively, for the 200 mg twice-daily dosing
regimen.
3.3 Final Model Evaluation Results
The goodness-of-fit for the final model was evaluated
graphically and is presented in Fig. 3. Overall, the plot of
predicted and observed concentrations indicated that the
model adequately described the observations over the
entire range of elagolix plasma concentrations. The conditional weighted residuals did not show any major trends
Elagolix Population Pharmacokinetics
Fig. 1 Organic anion-transporting polypeptide (OATP)–clearance
covariate relationships. The box shows the IQR with a median line.
Lower/upper whiskers extend to the lowest/highest value within
1.5 9 IQR. Data beyond the end of the whiskers are shown as filled
circles. For the unknown transporter group, a single outlier (with
clearance\ 20 L/h) was excluded from this figure in order to better
represent the covariate relationship. ET extensive transporter, IQR
interquartile range, IT/PT intermediate transporter/poor transporter
(IT and PT groups were combined for this analysis), OATP1B1
organic anion-transporting polypeptide 1B1 genotype status
Fig. 2 Covariate relationships
in healthy subjects and
endometriosis patients:
a elagolix clearance; and
b elagolix central volume of
distribution. In the figure, the
box shows the IQR with a
median line. Lower/upper
whiskers extend to the lowest/
highest value within 1.5 9 IQR.
Data beyond the end of the
whiskers are shown as filled
circles. IQR interquartile range
when plotted against sampling times or population predictions, indicating that the model was appropriately
unbiased.
Based on 500 simulations, the VPCs for the elagolix
plasma concentration–time profiles showed that the model
accurately describe the central tendency and variability of
I. Winzenborg et al.
Fig. 3 GOF plots for the final population pharmacokinetic model:
a population-predicted concentrations versus observed concentrations; b individual-predicted concentrations versus observed
concentrations; c CWRES versus time; and d CWRES versus
population predictions. CWRES conditional weighted residuals,
GOF goodness-of-fit
the data for all studies as well as for phase I and III studies
separately. For the 150 mg once-daily dose, some deviations occurred in describing the 5th percentile, possibly due
to outlying measurements not captured by the implemented
data exclusion rules (Electronic Supplementary Material).
The VPCs for the final model are presented in Fig. 4.
The final population pharmacokinetic model was used to
estimate confidence intervals of the model parameters. A
total of 967 of 1000 bootstrap replicates plus the original
dataset converged successfully. The estimated pharmacokinetic parameter values based on the original dataset
were in good agreement with the medians of the parameter
values estimated from the bootstrap replicates and none of
the bootstrap confidence intervals included zero (Table 3).
women with endometriosis employed compliance packaging technology to monitor patient compliance to study drug
administration. Such technology enabled a more accurate
record of dosing times for inclusion in the population
pharmacokinetic analysis.
The inclusion of data from several phase I and III studies
enabled development of a robust population pharmacokinetic model, with all structural pharmacokinetic parameters
estimated with good precision (RSE: 1–4%). Comparison
of post hoc CL/F and Vc/F estimates between healthy
subjects and women with endometriosis demonstrated
similarity between these two populations. Although the
comparison was not formally tested during the covariate
selection process (as it would be confounded by the differences in sampling frequency between phase I and III
studies), the observed similarity in pharmacokinetic
parameter estimates indicate that elagolix pharmacokinetics and exposures are comparable in healthy women and
women with endometriosis.
Of the 15 covariates investigated for influence on CL/
F or Vc/F, OATP1B1 genotype status was the only
covariate with a statistically significant effect on elagolix
CL/F. Women with OATP1B1 genotype status of PT or IT
4 Discussion
A population pharmacokinetic model was developed based
on the largest pharmacokinetic dataset for elagolix, to date,
and included substantial representation of healthy premenopausal women and premenopausal women with
endometriosis. The phase III clinical trials for elagolix in
Elagolix Population Pharmacokinetics
b Fig. 4 Visual predictive checks for the final elagolix population
pharmacokinetic model: a phase III, 150 mg qd; b phase III, 200 mg
bid; c phase I, prediction-corrected. bid twice daily, qd once daily,
TSLD time since last dose, VPC visual predictive checks
had an elagolix CL/F 14% lower than that for women with
OATP1B1 genotype status of ET. This effect is expected
given that elagolix elimination through hepatic metabolism
may be dependent on OATP1B1 transporter-mediated
hepatic uptake [15]. However, the minor difference in
elagolix CL/F shown in the model is not considered to be
clinically meaningful. None of the other tested covariates
(including body size, race/ethnicity, hepatic function, or
renal function) were significantly associated with elagolix
pharmacokinetic parameters and, hence, would not result in
different elagolix dosing recommendations for patients
with varying demographic characteristics.
A challenge that occurs when modeling phase III pharmacokinetic data for drugs with a short half-life and frequent dosing is that small deviations in dosing or sampling
times can lead to concentration measurements that are
beyond the expected concentration range for the TALD.
Attempts to model population pharmacokinetics while
including all pharmacokinetic data resulted in minimization termination during the first NONMEM iteration.
Therefore, a data exclusion rule was applied in order to
remove concentration data that are not physiologically
plausible based on the observed phase I data in 134 women.
This approach needs to be implemented with care, as it is
not suited for drugs where differences in pharmacokinetic
exposures between healthy subjects and patients are
expected. In the case of elagolix, the percentages of sparse
samples removed by this rule for healthy women in Study 5
were in the same range as those for phase III studies in
women with endometriosis.
Limitations of this analysis included the constraints
associated with utilizing sparse sampling data and outpatient dosing to develop population pharmacokinetic models. These challenges were addressed by using a substantial
intensive pharmacokinetic dataset along with the data
exclusion rule.
5 Conclusions
Overall, elagolix population pharmacokinetics are adequately described by a two-compartment model with a lag
time in absorption. The model demonstrated that elagolix
pharmacokinetic parameters are similar between healthy
women and women with endometriosis. OATP1B1 genotype status was the only statistically significant covariate
on elagolix CL/F. However, OATP1B1 genotype status did
I. Winzenborg et al.
not have a clinically meaningful impact on elagolix
exposure. None of the other tested covariates, including
body weight and BMI, were significantly associated with
elagolix pharmacokinetic parameters. The final population
pharmacokinetic model will be utilized for exposure–response models for key elagolix efficacy and safety outcome
measures.
Acknowledgements We thank AbbVie employee Sonja Kemmis
Causemaker for medical writing support for this manuscript. We also
thank AbbVie employee Xiaohua Du for dataset programming efforts.
6.
7.
8.
9.
Author contributions All authors contributed to the study design
and analysis and interpretation of the data. All authors participated in
the drafting and revising of the manuscript.
10.
Compliance with Ethical Standards
Funding AbbVie provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of
data as well as the writing, review, and approval of the manuscript.
11.
Conflict of interest Insa Winzenborg, Ahmed Nader, Akshanth R.
Polepally, Mohan Liu, Jacob Degner, Cheri E. Klein, Nael M. Mostafa, Peter Noertersheuser, and Juki Ng are employees of AbbVie, Inc.
and may hold stock or stock options.
12.
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