Pharmacokinetics and Safety of Follitropin Delta in Gonadotropin Down-Regulated Healthy Chinese Women.

BACKGROUND: Follitropin delta, a novel recombinant follicle-stimulating hormone (rFSH) preparation derived from a human cell line, has different pharmacokinetic and pharmacodynamic properties compared with existing rFSH preparations expressed by Chinese hamster ovary cells (CHO). OBJECTIVES: The objective of this study was to assess the pharmacokinetic characteristics, dose proportionality, and safety of follitropin delta in healthy Chinese women. METHODS: This was a phase I, randomized, open-label study. Twenty-four healthy Chinese women were randomized (1:1:1) to receive a single subcutaneous administration of follitropin delta 12, 18, or 24 µg. The pharmacokinetic parameters (maximum observed serum concentration [Cmax], time to reach Cmax [tmax], area under the serum concentration-time curve from dosing to infinity [AUC∞], and elimination phase half-life [t½]) of follitropin delta were derived using noncompartmental analysis. RESULTS: Following a single subcutaneous administration of follitropin delta 12, 18, or 24 µg, mean Cmax (0.388, 0.677, and 0.825 ng/mL, respectively) and AUC∞ (41.3, 62.9, and 83.1 h·ng/mL, respectively) increased in a dose-proportional manner. The median tmax was 24 h, and the mean t½ was in the range of 50.5-60.9 h. All treatment-related adverse events were categorized as mild, except for one case of urticaria from the follitropin delta 18-µg dose group which was considered moderate. Only one woman presented with elevation of alanine transaminase and aspartate aminotransferase at the follow-up visit, which was reported as a treatment-emergent adverse event. There were no injection-site reactions and none of the participants showed any confirmed presence of treatment-induced anti-FSH antibodies. CONCLUSIONS: The administration of single doses of follitropin delta to healthy Chinese women demonstrated dose-proportional pharmacokinetics over the dose range of 12-24 µg, and these doses were well tolerated. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov registration no. NCT04150861.

Dose Finding in the Clinical Development of 60 US Food and Drug Administration-Approved Drugs Compared With Learning vs. Confirming Recommendations.

This review characterizes clinical development that supported the label dose in 60 drug indications recently approved by the US Food and Drug Administration. With Lewis B. Sheiner's Learning vs. Confirming clinical drug development paradigm as a reference point, the clinical development paths, the design of dose-ranging trials, and the dose-exposure-response characterization were examined using US Food and Drug Administration approval packages. It was found that 89% of clinical development programs included several doses in the first-in-patient trial, 43% proceeded directly to confirmatory trials after the first-in-patient trial, and 52% included multiple doses in confirmatory development. A low number of doses and narrow dose ranges were generally included in dose-ranging trials, with only 20% including at least four doses over an at least 10-fold dose range. In a third of approval packages, no dose-response or exposure-response evaluation was identified, and model-based dose-exposure-response characterization was rarely alluded to, as only 2 of 60 approval packages mentioned the use of a model-based approach. The findings suggest that confirmatory development may often be guided more toward learning than confirming, and furthermore that dose exposure response is robustly assessed in only a minority of clinical drug development programs, indicating that there may be room left for optimizing the benefit/risk profile of confirmatory/marketed dose(s). Significant deviation from Learning vs. Confirming may exist in clinical development practice on several levels, and the reasons for why this may be the case are discussed in light of contemporary literature.