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Background and Objective: Daridorexant is a dual orexin receptor antagonist in clinical development for insomnia. As daridorexant is cleared mainly via cytochrome P450 (CYP) 3A4, the effect of hepatic impairment on the pharmacokinetics (PK), metabolism, and tolerability of daridorexant was evaluated. Sleep disorders are common in patients with liver cirrhosis and, therefore, sleep-promoting drugs with a better tolerability than currently available would be preferable, a premise that dual orexin receptor antagonists may fulfill., Methods: This was a single-dose, open-label, phase I study. Subjects with mild (Child-Pugh A, N = 8) or moderate (Child-Pugh B, N = 8) liver cirrhosis and matched healthy control subjects (N = 8) received 25 mg of daridorexant orally. Blood samples were collected for 72 h post-dose for PK assessments of daridorexant and three major metabolites., Results: Compared with healthy subjects, patients showed a decrease in total daridorexant area under the plasma concentration-time curve from zero to infinity (AUC 0- inf ) and maximum plasma concentration with a geometric mean ratio (GMR, 90% confidence interval [CI]) of 0.51 (0.28-0.92) and 0.50 (0.35-0.72) in Child-Pugh A and 0.74 (0.39-1.41) and 0.42 (0.29-0.60) in Child-Pugh B patients, respectively. Furthermore, the median time to reach maximum plasma concentration was slightly delayed (1.0 h [90% CI 0.0-2.0] in Child-Pugh A patients and 0.5 h [90% CI 0.0-1.5] in Child-Pugh B patients), while for Child-Pugh B patients, a doubling in half-life was observed (GMR [90% CI]: 2.09 [1.32-3.30]). Considering the high plasma protein binding (> 99%) and a 1.9-fold to 2.3-fold increase in the unbound fraction in patients, the PK of unbound daridorexant was also assessed. Compared with healthy subjects, Child-Pugh B patients had a higher AUC 0-inf  (GMR [90% CI] 1.60 [0.93-2.73]), a lower apparent plasma clearance (GMR [90% CI] 0.63 [0.37-1.07]), and the same doubling in the half-life observed for total daridorexant, whereas maximum plasma concentration and apparent volume of distribution were not different. Unbound daridorexant PK in Child-Pugh A patients did not differ from healthy subjects. In addition, the metabolic ratios (parent to metabolite), i.e., a marker of CYP 3A4 activity, of the two most abundant daridorexant metabolites were higher in patients with liver cirrhosis compared with healthy subjects. All treatment-emergent adverse events were transient and of mild or moderate intensity and no other treatment-related effects were apparent., Conclusions: No safety issue of concern was detected following administration of 25 mg of daridorexant in the study population. Moderate liver cirrhosis causes impaired hepatic clearance of unbound daridorexant, which prolongs the half-life. A 25-mg dose of daridorexant should, therefore, not be exceeded in Child-Pugh B patients. A dose adjustment is not required in Child-Pugh A patients, while avoidance of daridorexant in patients with Child-Pugh C cirrhosis is recommended., Clinical Trial Registration: ClinicalTrials.gov ID: NCT03713242., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)