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 China

Correspondence: 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 aixins0302@126.com

Purpose: 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