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

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 followin...

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Bibliographic Details
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
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Summary: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.
ISSN:1173-2563
1179-1918
DOI:10.1007/s40261-018-0650-4