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

OBJECTIVES: 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) > or = 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 (AUC(0-last)) and the peak FSH/LH serum concentrations (C(max)) 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 C(max) (ratio of means 1.0024, 90% confidence interval (CI) 0.9611-1.0454) and AUC(0-last) (ratio of means 1.0167, 90% CI 0.9933-1.0407), and for the r-hLH study (n = 63) for C(max) (ratio of means 0.9687, 90% CI 0.9194-1.0207) and AUC(0-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.