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

• Published in: Clinical drug investigation 2018-07, Vol.38 (7), p.631-638
• Main Authors: Yee, Ka Lai, McCrea, Jacqueline, Panebianco, Deborah, Liu, Wen, Lewis, Nicole, Cabalu, Tamara, Ramael, Steven, Wrishko, Rebecca E.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Area Under Curve; Azepines - administration & dosage; Azepines - adverse effects; Azepines - pharmacokinetics; Clinical trials; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Drug therapy; Fatigue - chemically induced; Headache - chemically induced; Healthy Volunteers; Humans; Insomnia; Internal Medicine; Male; Medicine; Medicine & Public Health; Metabolism; Metabolites; Middle Aged; Orexin Receptor Antagonists - administration & dosage; Orexin Receptor Antagonists - adverse effects; Orexin Receptor Antagonists - pharmacology; Original Research Article; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Pharmacotherapy; Psychiatry; Restless legs syndrome; Sleep; Sleep Aids, Pharmaceutical - administration & dosage; Sleep Aids, Pharmaceutical - adverse effects; Sleep Aids, Pharmaceutical - pharmacokinetics; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - pharmacokinetics; Young Adult
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-018-0650-4

Background and Objectives 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). Methods 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. Results 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. Conclusions Suvorexant was generally well tolerated after single and multiple dosing for 14 days. The findings support the once-nightly dosing regimen.