Abstract
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.
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Acknowledgments
Christopher Lines, PhD, of Merck & Co., Inc., Kenilworth, NJ, USA provided comments and edits on a draft of the manuscript. The authors would like to thank Hong Sun and Dexter Kennedy for serving as clinical monitors for this trial, Xiaodong Li for his contributions to the statistical analyses, Gail Murphy for her contributions to the approval of dose-escalation decisions, and Bo Liu for data collection. Medical writing support, under the direction of the authors, was provided by Hicham Naimy, PhD, and Adele Blair, PhD, of CMC AFFINITY, a division of Complete Medical Communications Ltd., Glasgow, UK in accordance with Good Publication Practice (GPP3) guidelines.
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Funding
This trial and medical writing assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA.
Conflict of interest
KLY, JM, DP, WL, NL, TC, and REW are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options. At the time of the trial, SR was an employee of SGS Life Sciences Services, a Contract Research Organization contracted by Merck & Co., Inc., Kenilworth, NJ, USA, to conduct the trial.
Ethical approval
All procedures performed in trials involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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Informed consent was obtained from all individual subjects included in the trial.
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Yee, K.L., McCrea, J., Panebianco, D. et al. Safety, Tolerability, and Pharmacokinetics of Suvorexant: A Randomized Rising-Dose Trial in Healthy Men. Clin Drug Investig 38, 631–638 (2018). https://doi.org/10.1007/s40261-018-0650-4
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DOI: https://doi.org/10.1007/s40261-018-0650-4