Single-dose pharmacokinetics, tolerability, and physiologically based pharmacokinetic modeling of Fazamorexant in Chinese patients with hepatic impairment and in healthy controls

Objectives YZJ-1139 (Fazamorexant) is a dual orexin receptor antagonist in development for adult insomnia. This study assessed the impact of hepatic impairment on Fazamorexant’s pharmacokinetic safety, and tolerability to guide clinical dosing. Methods This study used a non-randomized, open-label, single-dose design. Patients with mild or moderate hepatic impairment (Child-Pugh class A or B) and healthy subjects (n = 8 per group) received a single oral 20 mg dose of Fazamorexant. Results In total, 24 participants were enrolled and completed the study. In subjects with mild hepatic impairment, the geometric mean ratios (90% CI) of Fazamorexant plasma C max , AUC 0–t , and AUC 0 – ∞ relative to those with normal hepatic function were 97.82% (77.41%–123.60%), 145.22% (96.83%–217.79%), and 145.43% (97.70%–216.47%), respectively. In moderate impairment, the corresponding values for C max , AUC 0–t , and AUC 0 – ∞ were 104.68% (82.85%–132.28%), 153.41% (102.29%–230.07%), and 154.50% (103.79%–229.97%). Hepatic impairment did not significantly alter the peak time. Fazamorexant was generally well tolerated. Conclusion Fazamorexant showed good safety and minimal impact of hepatic impairment on C max , but AUC increased by approximately 50% in patients with mild or moderate hepatic impairment.