An Open-Label, Single and Multiple Dose Study to Evaluate the Pharmacokinetics and Safety of Fezolinetant in Healthy Chinese Female Subjects

Yang Li,1 Yue Liu,1 Megumi Iwai,2,3 Masato Takeuchi,3 Nan Song,4 Yuan Li,4 Aixin Shi1 1Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Astellas Pharma Global Development, Inc, Northbrook, IL, USA; 3Astellas Pharma Inc, Tokyo, Japan; 4Astellas (China) Investment Co, Ltd, Beijing, People’s Republic of ChinaCorrespondence: Aixin Shi, Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China, Email [email protected]: To evaluate pharmacokinetics (PK) and safety of fezolinetant after single-dose and multiple-dose administration of 15, 30, and 60 mg in healthy Chinese women.Patients and Methods: This was a fixed-sequence crossover study in 16 healthy Chinese female subjects, 18– 45 years old. All received single doses of fezolinetant 15 mg, 30 mg or 60 mg with a 3-day washout. From Day 10, subjects received multiple doses of 30 mg fezolinetant once-daily for 7 days. PK parameters were obtained during the single- and multiple-dose periods. Safety assessments were based on adverse events, vital signs, and laboratory tests.Results: Fezolinetant exhibited rapid absorption, with median time of the maximum concentration (tmax) 1.50 to 1.75 hours after single-dose administration of fezolinetant tablets in the fasted state, followed by a decline in plasma levels, with a mean t1/2 of 6.12– 7.69 hours at dose levels of 15, 30 and 60 mg. There was a dose-proportional increase in maximum concentration and total exposure for fezolinetant across the doses studied. Mean peak concentration (Cmax) values were 221, 439 and 834 ng/mL, for the 15, 30, and 60 mg doses, respectively. The drug exposure parameters had a low-to-moderate variability (21.1– 39.7%). Minimum accumulation was observed after multiple doses. Metabolite ES259564 showed rapid formation following a single dose of fezolinetant, with a median tmax of 1.50– 2.00 hours. Plasma levels then declined, with mean t1/2 ranging from 5.72– 6.31 hours. Dose-proportional increases in Cmax and AUCinf were observed following single-doses of fezolinetant. Steady state was achieved on the second day after starting multiple-dose administration. In total, 3 (18.8%) subjects experienced 4 drug-related treatment-emergent adverse events; all mild in severity.Conclusion: Linear PK was confirmed within the dose range of 15 to 60 mg in healthy Chinese women.Keywords: vasomotor symptoms, menopause, nonhormonal, neurokinin receptor