Safety, Tolerability, and Pharmacokinetics of Suvorexant: A Randomized Rising-Dose Trial in Healthy Men

Suvorexant (MK-4305) is an orexin receptor antagonist approved for the treatment of insomnia in the USA and other regions. This randomized, double-blind, placebo-controlled, sequential-panel, Phase 1 trial assessed the safety, tolerability, and pharmacokinetic data following single and multiple dosing of suvorexant in healthy men (aged 18–45 years). Within allocated panels, subjects (n = 8) were randomized to receive nightly doses of suvorexant (10, 20, 40, 80, and 100 mg) administered orally for 14 days, or placebo. Safety assessments included daily adverse event (AE) monitoring; pharmacokinetic data were obtained through periodic sampling. Of 40 subjects randomized, 39 completed the trial. The incidence of any AEs in the 10 and 20 mg groups was 67 and 83%, respectively, while 100% of subjects reported AEs in the dose groups of 40, 80, and 100 mg and the placebo group. The most frequently reported AEs were somnolence (n = 19 subjects), fatigue (n = 17), and headache (n = 15). Following single and multiple dosing, median time to reach maximum observed concentration ranged from 1.5 to 4.0 h and the apparent terminal half-life ranged from 7.7 to 14.5 h. Across the investigated doses, accumulation ratios for the area under the concentration–time curve and the maximum observed concentration were independent of dose and ranged from 1.21 to 1.60 and 1.00 to 1.46, respectively. Suvorexant was generally well tolerated after single and multiple dosing for 14 days. The findings support the once-nightly dosing regimen.