Pharmacological Interactions between the Dual Orexin Receptor Antagonist Daridorexant and Ethanol in a Double-Blind, Randomized, Placebo-Controlled, Double-Dummy, Four-Way Crossover Phase I Study in Healthy Subjects

Background Daridorexant (ACT-541468) is a potent dual orexin receptor antagonist under development for the treatment of sleep disorders. Concomitant intake of ethanol and hypnotics has been shown to result in additive/supra-additive depression of the central nervous system, resulting in pronounced sedation. Objective The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ethanol and daridorexant. Method This was a single-center, double-blind, placebo-controlled, randomized, four-way crossover study conducted in 19 healthy male/female subjects. Subjects received the following four treatments: ethanol with daridorexant, daridorexant alone, ethanol alone, and placebo. Daridorexant 50 mg and the matching placebo were administered as single oral tablets. Ethanol was infused intravenously and clamped at a level of 0.6 g/L for 5 h. The PK of ethanol and daridorexant were assessed and a battery of PD tests performed. Results Concomitant administration of ethanol prolonged the time to reach maximum plasma concentrations ( t max ) of daridorexant (median difference 1.25 h). No other relevant PK interactions were observed. Coadministration with ethanol produced a numerically greater impairment on saccadic peak velocity, body sway, visual analog scale (VAS) alertness, VAS alcohol intoxication, smooth pursuit, and adaptive tracking compared with daridorexant alone. All treatments were generally well tolerated without serious adverse events (AEs). The most commonly reported treatment-emergent AEs following coadministration of daridorexant and ethanol included somnolence, headache, fatigue, sudden onset of sleep, and dizziness. Conclusions Apart from a shift in t max , no relevant changes in PK parameters were observed following coadministration of daridorexant and ethanol. The coadministration led to reinforced drug actions that were, at most, indicative of infra-additive effects on certain PD markers. Patients will be advised not to consume ethanol with daridorexant. Clinical Trials Registration number: NCT03609775 (ClinicalTrials.gov Identifier)