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

Abstract

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 60 - 180 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. 32 kg m(-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.

Trial registration: ClinicalTrials.gov NCT00598208 NCT00702845 NCT00696800 NCT00696878 NCT01144416.

Keywords: age; controlled ovarian stimulation; corifollitropin alfa; population pharmacokinetics; race; weight.

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

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

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

Figure 4

Visual predictive check results for trial 107012 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

Figure 6

Comparison of area under the curve (AUC) across the pivotal phase III trials. Data are limited to Caucasian subjects only