Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation

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1 British Journal of Clinical Pharmacology PHARMACOKINETICS Br J Clin Pharmacol (2016) Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation Correspondence DrBarbaraJ.Stegmann,MD,Merck&Co.,Inc.,ClinicalResearch,Women s Health, 126 East Lincoln Avenue, Rahway, NJ 07728, USA. Tel.: ; Fax: ; bjstegmann@aol.com Received 16 October 2015; revised 29 February 2016; accepted 7 March 2016 Anthe S. Zandvliet 1,MaritaProhn 1, Rik de Greef 1,FrankvanAarle 2, Christine McCrary Sisk 2 and Barbara J. Stegmann 2 1 MSD BV, Oss, The Netherlands and 2 Merck & Co., Inc., Kenilworth, NJ, USA Keywords age, controlled ovarian stimulation, corifollitropin alfa, population pharmacokinetics, race, weight AIM The aim of the present study was to characterize the pharmacokinetic profile of corifollitropin alfa and examine the relationships between dose, intrinsic factors [body weight, body mass index (BMI), age and race] and corifollitropin alfa pharmacokinetics. METHODS Data from five phase II and III clinical trials of corifollitropin alfa were evaluated. All subjects included in the analysis received μg corifollitropin alfa for controlled ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol followed by daily recombinant follicle stimulating hormone (rfsh) from day 8 onwards. Serum corifollitropin alfa levels (across the entire range of treatment) and total follicle stimulating hormone immunoreactivity levels (up to the start of rfsh treatment) were indicators of drug exposure. The analyses were performed using a nonlinear mixed-effects modelling approach. RESULTS A total of 2630 subjects were treated with corifollitropin alfa, and 2557 subjects were evaluable for analysis. Body weight, BMI and race (Asian and Black vs. Caucasian) were significant determinants of corifollitropin alfa exposure. Dose-normalized corifollitropin alfa exposure was ~89% higher in women with a body weight of 50 kg vs. 90 kg (in subjects with a similar BMI of 24 kg m 2 ); 14% higher in women with a BMI of 18 kg m 2 vs.32kgm 2 (provided they were of similar body weight); and ~15.7% lower in Asian subjects and 13% higher in Black subjects vs. Caucasian subjects. CONCLUSIONS Body weight was the major determinant of corifollitropin alfa exposure; BMI and race (Asian and Black) were also determinants but to a lesser extent and without associated effects on clinical outcomes. Corifollitropin alfa dose adjustment is indicated, based on body weight but not for BMI or race. These recommendations are consistent with the product label. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Corifollitropin alfa is a recombinant gonadotrophin. A single injection of corifollitropin alfa initiates and sustains multiple follicular growth over the first 7 days of ovarian stimulation. Body weight is a major determinant of exposure to corifollitropin alfa and treatment outcome. WHAT THIS STUDY ADDS Body mass index and race are also determinants of corifollitropin alfa exposure but to a lesser extent than body weight. Ovarian response is similar, irrespective of BMI and race; thus, dose adjustments based on these factors are not necessary. DOI: /bcp The British Pharmacological Society

2 Effect of patient characteristics on corifollitropin alfa pharmacokinetics Introduction Corifollitropin alfa is a gonadotrophin hormone produced in Chinese hamster ovary cells using recombinant DNA technology [1]. Corifollitropin alfa acts as a sustained follicle stimulant that possesses similar pharmacological effects to recombinant follicle stimulating hormone (rfsh) but with a relatively longer elimination half-life that results in an extended duration of action. This is achieved using sitedirected mutagenesis and gene transfer techniques to produce a glycoprotein that consists of an α-subunit identical to human follicle stimulating hormone (FSH) noncovalently bound to a β-subunit composed of a complete β-chain of human FSH extended by the carboxy-terminal peptide of the β-subunit of human chorionic gonadotrophin (hcg) [1]. The resultant hormone is eliminated more slowly than rfsh, extending its elimination half-life in the range of h relative to that associated with rfsh (27 41 h). Owing to its long elimination half-life, one single subcutaneous injection of the recommended dose of corifollitropin alfa is able to initiate and sustain multiple follicular growth for an entire week and may replace the first seven injections of any daily FSH preparation in a controlled ovarian stimulation (COS) treatment cycle prior to in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) [2] (Figure 1). A gonadotrophin-releasing hormone (GnRH) antagonist (e.g. ganirelix) is administered daily from stimulation day 5 onwards, preventing an endogenous luteinizing hormone (LH) surge and untimely, uncontrolled ovulation. As soon as three or more follicles have a diameter of at least 17 mm, a single injection of hcg is administered to trigger final oocyte maturation. Approximately h following hcg administration, a transvaginal ultrasound-guided oocyte retrieval is performed, followed by standard IVF or ICSI to achieve pregnancy. Figure 1 Treatment regimen for controlled ovarian stimulation with the follicle stimulating hormone (FSH) agonist corifollitropin alfa and a gonadotrophin-releasing hormone (GnRH) antagonist to prevent an endogenous luteinizing hormone surge. hcg, human chorionic gonadotrophin; rfsh, recombinant follicle stimulating hormone The pharmacokinetic pharmacodynamic profile of corifollitropin alfa is unique and differs from that associated with once-daily administration of rfsh during the first week of a COS treatment cycle. For rfsh, the degree of ovarian stimulation increases with each daily dose, reaching a steady-state after approximately 5 7 days of stimulation [3]. The dose of rfsh is initially selected according to the clinician s prediction of ovarian response based on pretreatment determinants of ovarian reserve and is then titrated to reach the desired response. Conversely, women receiving corifollitropin alfa do not require intense monitoring during the first week of a treatment cycle. After an initial peak in FSH bioactivity, corifollitropin alfa concentrations and corresponding FSH bioactivity levels decline over a period of several days towards the FSH bioactivity threshold. From day 8 onward, additional doses of rfsh may be needed until the criteria for hcg trigger (three follicles at 17 mm) have been met. This profile for follicular recruitment and oocyte development has been supported by clinical trials which have demonstrated equivalency between the treatments [4 6]. The absorption, distribution, metabolism and elimination characteristics of corifollitropin alfa are well characterized in the overall target population and consistent with other gonadotrophins [7]. After a subcutaneous injection, maximum serum concentrations are attained after approximately 2 days [3]. The absolute bioavailability is 58% and the steady-state volume of distribution is 9.2 l [3]. The elimination half-life is approximately 3 days [3]. Serum concentrations of corifollitropin alfa increased proportionally with dose over a wide dose range of μg in female subfertility patients undergoing COS prior to IVF and/or ICSI treatment [3]. The optimal dose of subcutaneous corifollitropin alfa in COS was determined using a simulated pharmacokinetic pharmacodynamic modelling framework based on data from a phase II, dose-finding study (P38826) [4, 8, 9]. The model showed that body weight was a major determinant of exposure to corifollitropin alfa and treatment outcome [4, 9]. COS regimens with corifollitropin alfa doses of 100 μg for patients weighing 60 kg and 150 μg for patients weighing > 60 kg were expected to result in similar drug exposure and treatment outcomes [4, 9]. The selected doses were prospectively evaluated in phase III clinical trials in women < 36 years and 36 years of age [4 6, 10]. With the completion of the phase III trials, FSH immunoreactivity data from approximately 1400 subjects treated with corifollitropin alfa have become available. The target population evaluated in the phase III trials includes both a relatively young population ( 36 years of age, Trials and 38819), whereas the latest phase III trial (Trial 06029) was conducted in a relatively older population (35 to 42 years). The wider age range, as well as the extended dataset, allowed for a more extensive covariate analysis of corifollitropin alfa pharmacokinetics. Although previous analyses already have demonstrated that body weight is an important determinant, the current analysis allowed for a more precise description of the impact of this and possible other [e.g. age, body mass index (BMI), race] covariates on exposure to corifollitropin alfa using the recommended dosing regimen in the target population. The objective of the present analysis was to characterize further the pharmacokinetic profile of corifollitropin alfa Br J Clin Pharmacol (2016)

3 A.S.Zandvlietetal. after subcutaneous administration in the target population, and to investigate the relationships between dose, intrinsic factors (weight, BMI, race and age) and corifollitropin alfa pharmacokinetics. Methods Data from five phase II and III clinical trials of corifollitropin alfa were evaluated in a population pharmacokinetic analysis (Table 1) [4 6, 10]. These trials were selected for this analysis owing to: (i) the use of the final market formulation of corifollitropin alfa; (ii) the use of a GnRH antagonist protocol; (iii) the fact that they were phase II and phase III trials; and (iv) the fact that they had used corifollitropin alfa for the indication COS. Each study was conducted in accordance with principles of good clinical practice and was approved by the appropriate institutional review boards and regulatory agencies. Written informed consent was provided by all subjects. All subjects who were included in the pharmacokinetic analysis received a subcutaneous dose of μg corifollitropin alfa for COS in a GnRH antagonist protocol. Serum corifollitropin alfa levels were measured by a solidphaseenzymeimmunoassayspecific to corifollitropin alfa. rfsh and endogenous FSH did not interfere with this assay. FSH immunoreactivity levels were measured by an FSH fluoroimmunoassay which is FSH-specific but also crossreacts with corifollitropin alfa. This assay measures the total FSH immunoreactivity of corifollitropin alfa, endogenous FSH and recombinant FSH. Both the corifollitropin alfa concentrations (ng ml 1 )and FSH immunoreactivity levels (IU l 1 )wereincludedinone NONMEM [version (Globomax, Hanover, MD, USA)] dataset. A parameter called DVID was added to discriminate between corifollitropin alfa concentrations (DVID = 3) and FSH immunoreactivity levels (DVID = 4). The dataset included the following covariates: age, body weight, BMI, height, race and trial. In the population pharmacokinetic analysis, serum corifollitropin alfa levels (across the entire time range of COS treatment) and total FSH immunoreactivity levels (up to the start of rfsh treatment) were used as indicators of drug exposure (Figure 2). At baseline, total FSH immunoreactivity levels reflect endogenous FSH at day 2 or 3 of the menstrual cycle. After administration of corifollitropin alfa and up to the start of treatment with daily rfsh, total FSH immunoreactivity levels were dominated by corifollitropin alfa exposure, as endogenous FSH is suppressed during stimulation. Hence, a scaling factor (SCALE) could be estimated to allow for conversion of FSH immunoreactivity levels (IU l 1 ) into corifollitropin alfa concentrations (ng ml 1 ). The population pharmacokinetic analyses were performed using a nonlinear mixed-effects modelling approach. ThesoftwarepackageNONMEMwasusedfortheanalysis. The estimation method in NONMEM was first-order conditional with interaction. Model selection was based on the log-likelihood criterion and goodness-of-fit plots. First, a base model (structural model and random-effects model) was developed. Interindividual variability was assumed to be lognormally distributed. In addition, the covariance between corifollitropin alfa clearance (CL/F) and corifollitropin alfa volume of distribution (V/F) were estimated. Subsequently, a final model was defined upon inclusion of covariate relationships (body weight, BMI, race and age). Covariate identification was performed using an automated procedure (stepwise covariate modelling, PsN), which involved stepwise testing of covariate relationships in a forward inclusion and backward elimination procedure. The significance level (α)forforward and backward selection was set to 0.05 and A Bonferroni correction was applied for final selection of covariate relationships. Continuous covariate relationships were described by power functions, and categorical covariates were incorporated into the model as index variables (yes/no). For evaluation of the final model, parameter estimates and the corresponding standard error (SE) and shrinkage estimates were assessed. Reliability of the final model was evaluated based on goodness-of-fit plots, diagnostic plots, a bootstrap analysis and numerical and visual predictive checks. To characterize the pharmacokinetics of corifollitropin alfa, derived pharmacokinetic parameter estimates of t max, (dose-normalized) peak plasma concentration (C max ), (dose-normalized) area under he curve (AUC) and half-life were calculated from empirical Bayes estimates of absorption rate (Ka), CL/F and V/F. Simulations were performed with the final pharmacokinetic model to evaluate the impact of covariate effects on corifollitropin alfa exposure (AUC). Results Data In total, 2630 subjects were treated with corifollitropin alfa, of whom 2557 were evaluable for pharmacokinetic analysis in Trials (n = 226 of 233), (n = 253 of 268), (n = 712 of 755), (cycle 1, 675 of 682) and (691 of 692) (Table 1). An overview of demographic characteristics of the subjects included in the analysis is presented for each trial by dose group (Table 2). Structural model Corifollitropin alfa pharmacokinetics after subcutaneous (SC) administration could be well described by a onecompartmental model with first-order absorption from the subcutaneous depot and first-order elimination. A onecompartment model with zero-order input and first-order elimination was used to describe the kinetics of endogenous FSH. Input of endogenous FSH was set to zero from administration of corifollitropin alfa onwards, to account for suppression of endogenous FSH synthesis. The structural model is depicted in Figure 3. Final model Pharmacokinetic parameter estimates, covariate effects and random effect values are presented in Table 3. Typical values of Ka, CL/F and V/F for corifollitropin alfa were h 1 (absorption half-life of 16 h), 0.19 l h 1 and 19.1 l, respectively. Pharmacokinetic parameters of corifollitropin alfa could be estimated precisely, and resulted in small relative SEs (< 5%). 76 Br J Clin Pharmacol (2016)

4 Effect of patient characteristics on corifollitropin alfa pharmacokinetics Table 1 Overview of clinical trials used in the pharmacokinetic population analysis Study ref. No. ClinicalTrials.gov identifier Study start and completion date Trial objective(s) Trial design Treatment Pharmacokinetic assessments NCT May 2003 March 2004 To investigate the dose response relationship of a single injection of corifollitropin alfa Open-label, activerandomized, controlled, dose-finding trial (phase II) Single administration of 60, 120, or 180 μg corifollitropin alfa SC. Day 8+ rfsh QD Corifollitropin alfa (days1,3,5,8, day of hcg) FSH (day 1, 3, daily from day 5) NCT January 2007 December 2007 To investigate the efficacy and safety of a single injection of 100 μg corifollitropin alfa for COS Double-blind, active-controlled, randomized, equivalence trial (phase III) Single administration of 100 μg corifollitropin alfa pf SC. Day 8+ rfsh QD Corifollitropin alfa (day 1, 3, 5, 8, day of hcg) FSH (day 1, 3, 5, 8, day of hcg) NCT June 2006 January 2008 To investigate the efficacy and safety of a single injection of 150 μg corifollitropin alfa for COS Double-blind, activecontrolled, randomized, non-inferiority trial (phase III) Single administration of 150 μg corifollitropin alfa pf SC. Day 8+ rfsh QD FSH (day 1, 5, 8, day of hcg) (1 st cycle) NCT September 2006 May 2009 To assess safety and non-immunogenicity Open-label, uncontrolled, repeated cycle trial (phase III) Up to 3 cycles with 150 μg corifollitropin alfa pf SC. Day 8+ rfsh QD FSH (day 1, 5 or 6, 8, day of hcg) NCT June 2010 April 2012 To investigate the efficacy and safety a single injection of corifollitropin alfa for COS Double-blind, activecontrolled, randomized, multiple cycles noninferiority trial (phase III) Single administration of 150 μg corifollitropin alfa SC. Day 8+ rfsh QD FSH (day 1, 3, 5, 6, 7, 8, day of hcg) COS, controlled ovarian stimulation; FSH, follicle stimulating hormone; hcg, human chorionic gonadotrophin; QD, each day; rfsh, recombinant follicle stimulating hormone; SC, subcutaneous. Br J Clin Pharmacol (2016)

5 A.S.Zandvlietetal. Figure 2 Time frame of serum corifollitropin alfa concentrations and follicle stimulating hormone (FSH) immunoreactivity levels included in the pharmacokinetic analysis. Continuous line represents corifollitropin alfa; dashed line represents endogenous FSH; dotted line represents recombinant FSH Table 2 Demographics of subjects included in population pharmacokinetic analysis Phase II Phase III Trial Dose 60 μg 120 μg 180 μg 100 μg 60 kg 150 μg > 60 kg 150 μg 50 kg 150 μg > 60 kg n Body weight (kg), mean (SD) 64.1 (8.9) 64.9 (8.9) 63.9 (9.3) 54.0 (4.2) 68.8 (7.6) 67.8 (10.7) 67.0 (6.4) Height (cm), mean (SD) 168 (6.8) 166 (6.4) 168 (7.3) 162 (5.1) 167 (6.6) 164 (6.5) 166 (6.8) Body mass index (kg/m 2 ), mean (SD) 22.8 (3.1) 23.5 (3.2) 22.7 (2.7) 20.5 (1.5) 24.8 (2.8) 25.1 (3.6) 24.2 (24) Age (years), mean (SD) 32.0 (3.5) 32.1 (4.0) 32.4 (3.4) 30.9 (3.2) 31.5 (3.3) 38.0 (2.2) 32.9 (3.6) Race, n (%) Caucasian 72 (96) 70 (93.3) 73 (96.1) 138 (54.5) 609 (85.5) 524 (75.8) 633 (93.8) Asian 1 (1.3) 2 (2.7) 1 (1.3) 114 (45.1) 20 (2.8) 60 (8.7) 9 (1.3) Black 1 (1.3) 2 (2.7) 1 (1.3) 1 (0.4) 30 (4.2) 69 (10.0) 20 (3.0) Other 1 (1.3) 1 (1.3) 1 (1.3) 0 53 (7.4) 38 (5.5) 13 (1.9) SD, standard deviation. The baseline level of endogenous FSH was typically 6.85 IU l 1 and could also be estimated precisely. Interindividual variability was assumed to be lognormally distributed, and was included in Ka, V/F, CL/F, the elimination rate of endogenous FSH (Ke FSH ) and baseline FSH (FSH baseline ). Between-subject variability in Ka, CL/F and V/F was 22 30%. Body weight, BMI and race (Asian and Black vs. Caucasian) were identified as statistically significant determinants of corifollitropin alfa exposure. A study effect was included in the error model for FSH immunoreactivity to account for unexplained between-trial differences for Trials and All parameters and covariate effects could be precisely estimated (low relative SE). Visual predictive checks showed that the final model adequately described the time profiles of corifollitropin alfa concentrations and FSH immunoreactivity levels in the phase III trials. Visual predictive check results for trial are presented in Figure 4. For a typical Caucasian subject (body weight 67.1 kg and BMI 24.6 kg m 2 ), C max (4.43 ng ml 1 ) was attained 43.9 h after a single SC injection; exposure (AUC) was 688 ng h ml 1 and the typical elimination half-life was 69.4 h. Body weight and BMI As shown in Figure 5, body weight was a more important determinant of corifollitropin alfa exposure than was BMI. Corifollitropin alfa exposure decreases as body weight 78 Br J Clin Pharmacol (2016)

6 Effect of patient characteristics on corifollitropin alfa pharmacokinetics Figure 3 Structural models of corifollitropin alfa and endogenous follicle stimulating hormone (FSH). Ka, absorption rate; V/F, volume of distribution; CL/F, corifollitropin alfa clearance; Ke FSH, clearance of endogenous FSH; FSH baseline, baseline FSH. The corifollitropin alfa concentration is scaled from ng ml 1 to IU l 1 by a scaling factor (SCALE). SC, subcutaneous increases. In subjects with a similar BMI of 24 kg m 2, body weight would contribute to an increase in corifollitropin alfa dose-normalized exposure of approximately 89% in women with a body weight of 50 kg compared with women with a body weight of 90 kg treated with the same dose. Dosenormalized corifollitropin alfa exposure in women with a BMIof18kgm 2 is typically 14% (3.97 ng h ml 1 μg 1 vs ng h ml 1 μg 1 ) higher compared with women with a BMIof32kgm 2, provided that body weight is similar. This effect is relatively small relative to the body weight effect and overall variability (28%) and is not deemed clinically relevant. In women 36 years of age, body weight-based dosing was applied. Consequently, AUC was similar for subjects weighing 60 kg who were treated with 100 μg corifollitropin alfa (Trial ) and for subjects weighing > 60 kg who were treated with 150 μg corifollitropin alfa (Trials and 06029; Figures 5 and 6). Conversely, all women in Trial (> 36 years of age) were treated with 150 μg corifollitropin alfa, resulting in substantially higher exposure (~42%) in subjects with a body weight of 50 to 60 kg compared with subjects with a body weight > 60 kg (Trial 06029, Figure 6). Race Exposure to corifollitropin alfa was approximately 15.7% [95% confidence interval (CI) 12.0%, 19.0%] lower in Asian subjects and 13% (95% CI 8.0%, 19%) higher in Black subjects compared with Caucasian subjects. The lower exposure in Asian subjects was most apparent for subjects treated in Korea and Taiwan (all Asian subjects in Trial were treated with 100 μg corifollitropin alfa). Observed corifollitropin alfa exposure (AUC) in Asian subjects was 22.2% lower (522 ng h ml 1 vs. 670nghml 1 ) compared with Caucasian subjects in Trial In Trials and 06029, the observed differences in exposure for patients treated with the recommended dose were considerably smaller. These results might suggest that Asian subjects treated in Korea or Taiwan were slightly underexposed to corifollitropin alfa compared with Caucasian subjects. However, clinical outcomes (ovarian response, inhibin-b and E2 response, and follicular growth) were not compromised in Asian subjects relative to Caucasian subjects. Based on these findings, a dose adjustment is not indicated for Asian patients. Corifollitropin alfa exposure (AUC) in Black subjects treated with the recommended dose of 150 μg for subjects with a body weight > 60 kg was only 1.8% and 8.7% higher compared with Caucasian subjects included in Trials and 06029, respectively. Black subjects in trial (n = 20) had a 17.1% higher exposure compared with Caucasian subjects in this trial. Clinical outcomes (ovarian response, inhibin-b and E2 response, and follicular growth) were comparable between Black and Caucasian subjects in the different trials; therefore, the overall difference in corifollitropin alfa exposure in Black subjects relative to Caucasian subjects was not deemed clinically relevant. Discussion The present population pharmacokinetic model was successfully developed to describe two measures of exposure (i.e. corifollitropin alfa levels and FSH immunoreactivity) in an integrated fashion. Data from five phase II and III trials were adequately described by one-compartmental models of corifollitropin alfa and endogenous FSH. The integrated approach using population pharmacokinetic modelling allowed for a pooled analysis across the five trials, in spite of substantial differences in sampling design and a lack of bioanalysis of corifollitropin alfa using the specific assayina subset of the trials. The results show that body weight was the primary determinant of corifollitropin alfa exposure. BMI and race (Asian and Black) were also determinants of drug exposure but to a lesser extent than body weight. The impact of BMI was relatively small in comparison with the overall variability of corifollitropin alfa exposure. Ovarian response was similar, irrespective of BMI and race; thus, dose adjustments based on these factors are not necessary. Patient age had no impact on the pharmacokinetics of corifollitropin alfa: the risk of excessive ovarian stimulation after treatment with 150 μg was very low in patients > 36 years of age, irrespective of body weight, and individualized dosing based on body weight was only deemed necessary in women 36 years of age. Corifollitropin alfa distributes within the extracellular fluid space, which increases with body weight [11]. As a result, Br J Clin Pharmacol (2016)

7 A.S.Zandvlietetal. Table 3 Parameter estimates of final models for corifollitropin alfa and endogenous follicle stimulating hormone θ Pharmacokinetic parameter Covariate relationship* Typical value 95% CI RSE IIV (CV%) 95% CI Shrinkage Corifollitropin alfa θ1 Ka (h 1 ) % 29.2% % θ2 V/F (l) V/F = θ2 (WT/60) θ13 /F % 29.3% % θ13 V/F ~WT % θ3 CL/F (l h 1 ) CL/F = θ3 (WT/60) θ12 /F % 22.1% % 1FIX θ12 CL/F ~WT % θ6 F F = θ6 (BMI/23.3) θ16 BLACK θ17 ASIAN θ18 θ16 F ~BMI % θ17 Relative F Asian % θ18 Relative F Black % θ7 Scaling factor ng ml 1 to IU l FIX** θ14 Trial effect % θ15 Trial effect % Endogenous FSH θ4 Ke FSH (h 1 ) Ke = θ4 (AGE/34) θ20 θ21 ASIAN (WT/60) θ % 29% % θ20 Ke FSH ~AGE % θ21 Ke FSH ~ Asian % θ22 Ke FSH ~WT % θ5 FSH baseline (IU l 1 ) FSH baseline = θ5 (AGE/34) θ % 26.7% % θ19 FSH baseline ~ AGE % Error model θ8 Proportional corifollitropin alfa 13.10% % 14.7% θ9 Additive corifollitropin alfa 0 FIX θ10 Proportional FSH 4.86% % 36.4% θ11 Additive FSH % 36.4% *Covariance between random variability of CL/F and V/F was estimated to be (95% CI 0.051, 0.061; P =0.87); ASIAN = 1 for Asian subjects and ASIAN = 0 for non-asian subjects; BLACK = 1 for lack subjects and BLACK = 0 for non-black subjects; IIV was parameterized as exp(η) andthe coefficient of variation was calculated as square root(exp(ω)-1) 100%; 95% CI P2.5, P97.5 of 1000 bootstrap results; **scaling factor fixed to 6.11 as derived in a previous analysis. BMI, body mass index; CI, confidence interval; CL/F, corifollitropin alfa clearance; FIX, parameter fixed (not estimated); FSH, follicle stimulating hormone; FSH baseline, baseline FSH; Ka, absorption rate; Ke FSH, clearance of endogenous FSH; RSE, relative standard error as calculated by the covariance step of NONMEM; V/F, volume of distribution; WT, weight serum concentrations of corifollitropin alfa are inversely related to body weight. For this reason, corifollitropin alfa is approved as a 100 μg dosage for patients weighing 60 kg and as a 150 μg dosage for patients weighing > 60 kg in women < 36 years of age [3]. These selected doses of corifollitropin alfa provide, on average, equivalent drug exposure and a similar ovarian response in the two body weight groups [11]. The present results, based on a large phase II/III dataset, confirmed the earlier finding that body weight is a stronger determinant of drug exposure than is BMI. As described by Ledger et al. [11], this may be explained by a theoretical example of two subjects with a BMI of 23 kg m 2, one 1.54 m (5.05 feet) tall and weighing 55 kg, and the other 1.80 m (5.9 feet) tall and weighing 75 kg. The volume of extracellular fluid is larger in the taller, heavier subject than in the shorter subject with lower body weight, whereas the BMI of both subjects is the same. The larger volume of extracellular volume of extracellular fluid results in a larger volume of distribution and clearance, in accordance with general principles of allometry. Consequently, treatment of each subject with the same dose of corifollitropin alfa would 80 Br J Clin Pharmacol (2016)

8 Effect of patient characteristics on corifollitropin alfa pharmacokinetics Figure 4 Visual predictive check results for trial for corifollitropin alfa levels (A) and follicle stimulating hormone (FSH) immunoreactivity levels (B) Figure 5 Effect of body weight and body mass index (BMI) on corifollitropin alfa exposure. Subjects weighing 60 kg who were treated with 100 μg corifollitropin alfa; subjects weighing > 60 kg who were treated with 150 μg corifollitropin alfa. AUC = area under the curve result in lower corifollitropin alfa concentrations in the subject weighing 75 kg than in the subject weighing 55 kg. By contrast, BMI had only a limited impact on corifollitropin alfa. Subjects with a higher BMI have a larger percentage of their body weight composed of fat tissue. Adipose tissue has a relatively low content of extracellular water i.e. approximately 0.11 l kg 1 in adipose tissue vs l kg 1 overall in non-obese subjects [12]. Moreover, low perfusion may result in limited distribution of corifollitropin alfa to extracellular water in adipose tissue [13]. Hence, adipose tissue does not markedly increase the volume of distribution or clearance of corifollitropin alfa. For rfsh, an association between exposure and body weight was weaker as compared with the relatively strong impact of body weight on corifollitropin alfa concentrations. Figure 6 Comparison of area under the curve (AUC) across the pivotal phase III trials. Data are limited to Caucasian subjects only This may be due to differences in drug disposition i.e. corifollitropin alfa is confined to extracellular water, whereas the volume of distribution of rfsh was reported to be approximately two-fold larger. Corifollitropin alfa exposure was lower in Asian subjects, particularly in those treated in Korea and Taiwan, and higher in Black subjects compared with Caucasian subjects. In spite of these differences in exposure, the follicular responses were similar, irrespective of race. Hence, this finding was not deemed clinically relevant and individualized dosing based on race is not warranted. Dose selection for the phase III clinical programme was based on an extensive modelling and simulation analysis. The selected doses were evaluated prospectively after completion of the phase III trials, and resulted in an acceptable safety profile, favourable pharmacodynamics, a low risk of cycle cancellation and a desirable number of follicles and oocytes Br J Clin Pharmacol (2016)

9 A.S.Zandvlietetal. retrieved [4 6]. The recommended dose of corifollitropin alfa isdependentonbodyweightinwomen 36 years of age: 100 μg forwomenwithabodyweight 60 kg and 150 μg for women with a body weight > 60 kg. In women > 36 years of age, the 150 μg dose is recommended irrespective of body weight to account for the decrease in ovarian reserve with age. The results of the present population pharmacokinetic analysis confirm that body weight is the major intrinsic factor, which is inversely correlated with corifollitropin alfa exposure, and that the recommended dosing regimen adequately accounts for this effect. Competing Interests All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare that ASZ,MP,RdG,FvA,CMSandBJSarecurrentorformeremployees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock/stock options in the company. These are the only declarations for the previous 3 years. The authors thank Kristen Lewis of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, for her assistance with the submission of the manuscript. Financial support for this study was provided by Merck & Co. Inc., Kenilworth, NJ, USA. References 1 Fares FA, Suganuma N, Nishimori K, LaPolt PS, Hsueh AJ, Boime I. Design of a long-acting follitropin agonist by fusing the C- terminal sequence of the chorionic gonadotropin beta subunit to the follitropin beta subunit. Proc Natl Acad Sci U S A 1992; 89: Fauser BC, Mannaerts BM, Devroey P, Leader A, Boime I, Baird DT. Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency. Hum Reprod Update 2009; 15: European Medicines Agency. Elonva (corifollitropin alfa): summary of product characteristics Available at _Product_Information/human/001106/WC pdf (last accessed 15 April 2016). 4 Corifollitropin alfa Ensure Study Group. Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-bodyweight women. Reprod Biomed Online 2010; 21: Boostanfar R, Shapiro B, Levy M, Rosenwaks Z, Witjes H, Stegmann BJ, et al. Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant folliclestimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization. Fertil Steril 2015; 104: Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman- Boon PC, Fauser BC. A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod 2009; 24: van Schanke A, van de Wetering-Krebbers SF, Bos E, Sloot WN. Absorption, distribution, metabolism and excretion of corifollitropin alfa, a recombinant hormone with a sustained follicle-stimulating activity. Pharmacology 2010; 85: Arandomizeddose response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation. Hum Reprod 2008; 23: de Greef R, Zandvliet AS, de Haan AF, Ijzerman-Boon PC, Marintcheva-Petrova M, et al. Dose selection of corifollitropin alfa by modeling and simulation in controlled ovarian stimulation. Clin Pharmacol Ther 2010; 88: Norman RJ, Zegers-Hochschild F, Salle BS, Elbers J, Heijnen E, Marintcheva-Petrova M, et al. Repeated ovarian stimulation with corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for immunogenicity. Hum Reprod 2011; 26: Ledger WL, Fauser BC, Devroey P, Zandvliet AS, Mannaerts BM. Corifollitropin alfa doses based on body weight: clinical overview of drug exposure and ovarian response. Reprod Biomed Online 2011; 23: Waki M, Kral JG, Mazariegos M, Wang J, Pierson RN, Heymsfield SB. Relative expansion of extracellular fluid in obese vs. non-obese women. Am J Physiol Endocrinol Metab 1991; 261: E Jonsson F, Johanson G. Physiologically based modeling of the inhalation kinetics of styrene in humans using a Bayesian population approach. Toxicol Appl Pharmacol 2002; 179: Br J Clin Pharmacol (2016)