Jun Ni,1 Lu Jin,2 Dong Zhao,1 Wen Zhang,1 Baoshun Li,1 Xingxing Huang,2 Xiaohua Hao3 

1Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Yangtze River Pharmaceutical Group Co, Ltd., Taizhou, People’s Republic of China; 3Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China

Correspondence: Xiaohua Hao, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China, Email xiaohualuck@sina.com Xingxing Huang, Yangtze River Pharmaceutical Group Co, Ltd, Taizhou, People’s Republic of China, Email xingxingh@haiyanpharma.com

Purpose: This is the first-in-human study to investigate the pharmacokinetic and pharmacodynamic profiles, safety, and tolerability of Fazamorexant (a novel dual orexin receptor antagonist) in healthy subjects.
Methods: Here, we summarize pharmacokinetic, pharmacodynamic, and safety data from the randomized, double-blind placebo-controlled studies in healthy adults: single ascending doses (2– 80 mg; N = 64), multiple ascending doses (10– 60 mg; N = 40).
Results: Following single and multiple dosing, the pharmacokinetic profile was characterized by quick absorption and elimination, with median tmax of 0.625– 1.25 h and arithmetic mean t1/2 of 1.91– 3.68 h. Cmax and AUC0-t were positively correlated with doses and no apparent Fazamorexant plasma accumulation was detected on Day 7. The hypnotic effects were observed after administration and the effects of high dose groups were slightly higher than that of low dose groups, the results of pharmacodynamics showed a dose-dependent effect and the change in SSS from baseline was greatest in the 80 mg group (2.5). There were no clinically relevant effects of gender on Fazamorexant pharmacokinetics. No serious dose-dependent adverse events (AEs) or deaths were observed during the study.
Conclusion: Fazamorexant at a single dose of 2– 80 mg or 10– 60 mg at multiple doses presented satisfactory safety and tolerability in healthy subjects. The findings in this comprehensive first-in-humans study support the continued investigation of Fazamorexant as a therapeutic option for insomnia therapy.

Keywords: first-in-humans, Fazamorexant, orexin receptor antagonist, pharmacokinetics, pharmacodynamics, safety