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Abstract
This was a Phase I, open-label, randomized, two-period, two-sequence crossover study [ClinicalTrials.gov NCT02317809 (https://www.clinicaltrials.gov/ct2/show/NCT02317809); EudraCT 2014-003506-32] assessing the bioequivalence of the liquid and freeze-dried formulations of fixed-dose, fixed-ratio (2:1) combination recombinant human follicle-stimulating hormone plus recombinant human luteinizing hormone (r-hFSH/r-hLH). The safety and tolerability of the two formulations were also assessed. Healthy premenopausal women were randomized to one of two crossover dosing schedules. Subjects in Treatment Sequence 1 received a single subcutaneous dose (900/450 IU r-hFSH/r-hLH) of the liquid formulation of r-hFSH/r-hLH on Day 1 of Dose Period 1 and, after a washout period of at least 14 days, a single subcutaneous dose (900/450 IU r-hFSH/r-hLH) of the freeze-dried formulation of r-hFSH/r-hLH (reconstituted in water for injection prior to administration) on Day 1 of Dose Period 2. Subjects in Treatment Sequence 2 received the treatments in reverse order. The primary endpoints were AUC0–t (area under the serum concentration–time curve from time 0 to the time of the last quantifiable concentration) and Cmax (maximum serum concentration) for FSH and LH, both baseline corrected. A total of 34 subjects were randomized, and 22 subjects were included in the bioequivalence evaluation. Overall, the mean observed PK profiles and individual PK parameters were comparable for the liquid and freeze-dried formulations, although a median difference in the tmax (time to reach maximum observed concentration) of FSH of ~4.5 h was observed between the formulations. The calculated 90% confidence intervals of the mean liquid formulation/freeze-dried formulation ratios for Cmax and AUC0–t were within the bioequivalence range (80–125%) for both LH and FSH, confirming bioequivalence between the two formulations. The safety and tolerability profiles of the two formulations were similar. The liquid formulation can, therefore, be expected to provide the same efficacy as the freeze-dried formulation, with no differences in tolerability.
Highlights
The pen injector has been demonstrated to reliably dispense accurate doses under a range of conditions, including cold, standard and warm atmospheres, and subsequent to freefall, vibration, dry-heat, cold-storage, and shipping preconditioning [7]. These reasons, together with the discrete design of pen injectors and the potential to use a smaller gauge needle mean that pen injectors are a preferred option compared with needle and syringe, and liquid formulations are, desirable [8]
The study was approved by the local ethics committee (Westminster Research Ethics Committee; Manchester, United Kingdom; 14/LO/2052) and conducted in accordance with the European Medicines Agency (EMA) guidelines on bioequivalence [11], the clinical study protocol, the International Council for Harmonization–Good Clinical Practice, and any additional applicable regulatory requirements
Owing to difficulties recruiting subjects who met the inclusion criteria, in addition to a higher than expected number of subjects not downregulating sufficiently on Marvelon, 34 subjects were subsequently randomized
Summary
Pergoveris® (Merck KGaA, Darmstadt, Germany) is a fixed-dose, fixed-ratio (2:1) combination of recombinant human folliclestimulating hormone (r-hFSH; 150 IU) plus recombinant human luteinizing hormone (r-hLH; 75 IU) indicated for the stimulation of follicular development in adult women with severe FSH and LH deficiency defined by an endogenous serum LH level
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