Bioequivalence of recombinant human FSH and recombinant human LH in a fixed 2 : 1 combination: two phase I, randomised, crossover studies

ABSTRACTABSTRACTObjectives: To assess bioequivalence of recombinant human follicle stimulating hormone (r-hFSH, follitropin alfa) and recombinant human luteinising hormone (r-hLH, lutropin alfa) in a fixed 2 : 1 combination (Pergoveris) compared with injection of each of the hormones separately.Research design and methods: Two, two-way crossover, phase I studies in healthy female volunteers after gonadotrophin-releasing hormone agonist down-regulation. Volunteers were randomised to the order in which they received subcutaneous injections. In the r-hFSH study, volunteers received one injection of r-hFSH (300 IU) and one of r-hFSH (300 IU)/r-hLH (150 IU) ≥ 7 days apart; in the r-hLH study they received r-hLH (450 IU) and r-hFSH (900 IU)/r-hLH (450 IU) > 21 days apart.Main outcome measures: The serum concentration–time profiles of FSH in the r-hFSH study and LH in the r-hLH study from zero to the last measurable concentration (AUC0–last) and the peak FSH/LH serum concentrations (Cmax) were assessed by non-compartmental analysis. The pre-defined range for bioequivalence was 0.8–1.25 for 90% confidence intervals (CI) of the ratio (fixed combination/single gonadotrophin) of the mean for each pharmacokinetic parameter.Results: Bioequivalence criteria were met for the r-hFSH study (n = 34) for Cmax (ratio of means 1.0024, 90% confidence interval (CI) 0.9611–1.0454) and AUC0–last (ratio of means 1.0167, 90% CI 0.9933–1.0407), and for the r-hLH study (n = 63) for Cmax (ratio of means 0.9687, 90% CI 0.9194–1.0207) and AUC0–last (ratio of means 0.9753, 90% CI 0.8990–1.0581). In the r-hFSH study, 20 adverse events (AEs) were reported after injection of r-hFSH and 20 after r-hLH/r-hFSH. In the r-hLH study, 179 AEs were reported after injection of r-hLH and 193 after the fixed-dose combination. Across both studies, headache was the most commonly reported AE. No serious AEs occurred.Conclusions: These studies demonstrated bioequivalence between r-hFSH and r-hLH administered alone or in fixed 2 : 1 combination. The 2 : 1 combination of follitropin alfa and lutropin alfa allows administration of both recombinant gonadotrophins in a single injection. Key words: : BioequivalenceCombination, fixedFSHLHPharmacokineticsRecombinant