Pharmacokinetics, Tolerability, and Biomarker Profile of the Neurokinin 3 Receptor Antagonist Fezolinetant in Healthy Japanese Individuals: A 2-Part, Randomized, Phase 1 Study.

Abstract

This 2-part, randomized, placebo-controlled, double-blind, Phase 1 study analyzed the pharmacokinetics, safety, and biomarker profile of fezolinetant in healthy Japanese individuals. Part 1: male participants received single doses of placebo or fezolinetant 15 or 60 mg. Part 2: male and premenopausal and postmenopausal female participants received a single dose of placebo or fezolinetant 180 mg, followed by a 2-day washout, and multiple dosing once daily for 10 days. Fezolinetant was rapidly absorbed with peak concentrations 1-2 hours after single-dose administration; plasma levels subsequently declined (half-life range, 3.29-7.24 hours). Only slight accumulation (area under the concentration-time curve accumulation ratio, 1.46‒1.57) was observed after once-daily multiple-dose administration. No serious/severe treatment-emergent adverse events were observed; the only fezolinetant-related treatment-emergent adverse event was mild uterine bleeding in 1 premenopausal woman and 1 postmenopausal woman. Concentration-QT analysis showed that fezolinetant does not have a clinically significant effect on QT interval. Fezolinetant produced dose-dependent reductions in luteinizing hormone and slight reductions in follicle-stimulating hormone; levels subsequently returned to baseline 48 hours or fewer after dosing. This analysis shows that fezolinetant doses up to 180 mg had an acceptable safety, pharmacokinetic, and biomarker profile. This study clarifies the safety, pharmacokinetic, and biomarker profiles of fezolinetant in Japanese individuals.