Pharmacological Interactions between the Dual Orexin Receptor Antagonist Daridorexant and Ethanol in a Double-Blind, Ran
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ORIGINAL RESEARCH ARTICLE
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 Benjamin Berger1 · Sander Brooks2,3 · Rob Zuiker2 · Muriel Richard1 · Clemens Muehlan1 · Jasper Dingemanse1 Accepted: 23 September 2020 © Springer Nature Switzerland AG 2020
Abstract 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 (tmax) 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 tmax, 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)
The authors confirm that the Principal Investigator for this study is Rob Zuiker and that he had direct clinical responsibility for the subjects. Benjamin Berger and Sander Brooks contributed equally to this body of work. * Benjamin Berger [email protected] 1
Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, Switzerland
2
Centre for Human Drug Research (CHDR), Leiden, The Netherlands
3
Leiden University Medical Center, Leide
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