Dataset Information

Open-Label, Randomized, Two-Way, Crossover Study Assessing the Bioequivalence of the Liquid Formulation versus the Freeze-Dried Formulation of Recombinant Human FSH and Recombinant Human LH in a Fixed 2:1 Combination (Pergoveris®) in Pituitary-Suppressed Healthy Women.

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.

SUBMITTER: Bagchus W

PROVIDER: S-EPMC5768635 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Open-Label, Randomized, Two-Way, Crossover Study Assessing the Bioequivalence of the Liquid Formulation versus the Freeze-Dried Formulation of Recombinant Human FSH and Recombinant Human LH in a Fixed 2:1 Combination (Pergoveris<sup>®</sup>) in Pituitary-Suppressed Healthy Women.

Bagchus Wilhelmina W Yalkinoglu Özkan Ö Wolna Peter P

Frontiers in endocrinology 20180111

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 ...[more]

PMID: 29375477

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Project description:Somatropin is recombinant human growth hormone (GH) used for the treatment of growth failure in children and GH deficiency in adults. Two concentrations of a liquid formulation have been developed: 5.83 and 8.0 mg/mL. This trial compared the pharmacokinetics (PK), safety and tolerability of these two liquid concentrations against the freeze-dried (FD) formulation in healthy volunteers.In an open-label, single-centre, three-way crossover study, volunteers (aged 18-45 years) were given subcutaneous injections of the reconstituted FD and two liquid formulations in random sequential order, each at 4 mg/dose, with a 1-week wash-out period between doses. To suppress endogenous GH secretion, intravenous somatostatin was infused continuously 1 hour before to 24 hours after each dose, achieving a cumulative dose of 3 mg. Primary PK endpoints were area under the serum concentration-time curve (AUC0-t) and maximum serum concentration (Cmax). For each of the two liquid formulations, bioequivalence with the FD formulation was concluded if the 95% confidence intervals (CIs) for the estimated test/reference ratios of geometric means of AUC0-t and Cmax were within the standard pre-specified acceptance range (0.80-1.25).Fifteen men and 15 women enrolled (safety population, n = 30; PK population, n = 28). Bioequivalence with the FD formulation could be shown for both liquid formulations. The ratios of geometric means (95% CI) were 1.046 (0.980, 1.117) and 0.991 (0.929, 1.058) for AUC0-t and 0.954 (0.875, 1.040) and 0.955 (0.876, 1.041) for Cmax for the 5.83 and 8.0 mg/mL formulations, respectively. No significant differences between the three treatments in half-lives, time to reach Cmax, clearance or volume of distribution were observed. After injection, the most common side-effects were pain or injection-site reactions (all of mild intensity). There were no clinically significant abnormal vital signs, ECG or laboratory findings. There were 56 treatment-related adverse events (AEs): 49 mild, 6 moderate and 1 severe (vomiting). No serious AEs occurred. The pattern of AEs was as expected and all resolved by study end.Both concentrations of a new liquid multi-dose formulation are bioequivalent to the FD reference formulation and all are well tolerated.NCT01034735.

Project description:The hormone - specific FSHβ subunit of the human FSH heterodimer consists of N-linked glycans at Asn7 and Asn24 residues that are co-translationally attached early during subunit biosynthesis. Differences in the number of N-glycans (none, one or two) on the human FSHβ subunit contribute to macroheterogeneity in the FSH heterodimer. The resulting FSH glycoforms are termed hypo-glycosylated (FSH21/18, missing either an Asn24 or Asn7 N-glycan chain on the β - subunit, respectively) or fully glycosylated (FSH24, possessing of both Asn7 and Asn24 N-linked glycans on the β - subunit) FSH. The recombinant versions of human FSH glycoforms (FSH21/18 and FSH24) have been purified and biochemically characterized. In vitro functional studies have indicated that FSH21/18 exhibits faster FSH- receptor binding kinetics and is much more active than FSH24 in every assay tested to date. However, the in vivo bioactivity of the hypo-glycosylated FSH glycoform has never been tested. Here, we evaluated the in vivo bioactivities of FSH glycoforms in Fshb null mice using a pharmacological rescue approach. In Fshb null female mice, both hypo- and fully-glycosylated FSH elicited an ovarian weight gain response by 48 h and induced ovarian genes in a dose- and time-dependent manner. Quantification by real time qPCR assays indicated that hypo-glycosylated FSH21/18 was bioactive in vivo and induced FSH-responsive ovarian genes similar to fully-glycosylated FSH24. Western blot analyses followed by densitometry of key signaling components downstream of the FSH-receptor confirmed that the hypo-glycosylated FSH21/18 elicited a response similar to that by fully-glycosylated FSH24 in ovaries of Fshb null mice. When injected into Fshb null males, hypo-glycosylated FSH21/18 was more active than the fully-glycosylated FSH24 in inducing FSH-responsive genes and Sertoli cell proliferation. Thus, our data establish that recombinant hypo-glycosylated human FSH21/18 glycoform elicits bioactivity in vivo similar to the fully-glycosylated FSH. Our studies may have clinical implications particularly in formulating FSH-based ovarian follicle induction protocols using a combination of different human FSH glycoforms.

Dataset Information

Open-Label, Randomized, Two-Way, Crossover Study Assessing the Bioequivalence of the Liquid Formulation versus the Freeze-Dried Formulation of Recombinant Human FSH and Recombinant Human LH in a Fixed 2:1 Combination (Pergoveris®) in Pituitary-Suppressed Healthy Women.

Publications

Open-Label, Randomized, Two-Way, Crossover Study Assessing the Bioequivalence of the Liquid Formulation versus the Freeze-Dried Formulation of Recombinant Human FSH and Recombinant Human LH in a Fixed 2:1 Combination (Pergoveris<sup>®</sup>) in Pituitary-Suppressed Healthy Women.

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