Clinical Drug Investigation

, Volume 39, Issue 5, pp 441–451 | Cite as

Effect of CYP3A Inhibition and Induction on the Pharmacokinetics of Suvorexant: Two Phase I, Open-Label, Fixed-Sequence Trials in Healthy Subjects

  • Rebecca E. Wrishko
  • Jacqueline B. McCreaEmail author
  • Ka Lai Yee
  • Wen Liu
  • Deborah Panebianco
  • Eric Mangin
  • Manu Chakravarthy
  • Maria P. Martinez-Cantarin
  • Walter K. Kraft
Original Research Article


Background and Objectives

Suvorexant is an orexin receptor antagonist indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. As suvorexant is metabolized primarily by Cytochrome P450 3A (CYP3A), and its pharmacokinetics may be affected by CYP3A modulators, the effects of CYP3A inhibitors (ketoconazole or diltiazem) or an inducer (rifampin [rifampicin]) on the pharmacokinetics, safety, and tolerability of suvorexant were investigated.


In two Phase I, open-label, fixed-sequence trials (Studies P008 and P038), healthy subjects received a single oral dose of suvorexant followed by co-administration with multiple once-daily doses of strong/moderate CYP3A inhibitors (ketoconazole/diltiazem) or a strong CYP3A inducer (rifampin). Treatments were administered in the morning: suvorexant 4 mg with ketoconazole 400 mg (Study P008; N = 10), suvorexant 20 mg with diltiazem 240 mg (Study P038; N = 20), and suvorexant 40 mg with rifampin 600 mg (Study P038; N = 10). Area under the plasma concentration–time curve from time zero to infinity (AUC0–∞), maximum plasma concentration (Cmax), half-life (t½), and time to Cmax (tmax) were derived from plasma concentrations of suvorexant collected at prespecified time points up to 10 days following CYP3A inhibitor/inducer co-administration. Adverse events (AEs) were recorded.


Co-administration with ketoconazole resulted in increased exposure to suvorexant [AUC0–∞: geometric mean ratio (GMR); 90% confidence interval (CI) 2.79 (2.35, 3.31)] while co-administration with diltiazem resulted in a lesser effect [GMR (90% CI): 2.05 (1.82, 2.30)]. Co-administration with rifampin led to a marked decrease (88%) in suvorexant exposure. Consistent with morning administration and known suvorexant pharmacology, somnolence was the most frequently reported AE.


These results are consistent with expectations that strong CYP3A inhibitors and inducers exert marked effects on suvorexant pharmacokinetics. In the context of a limited sample size, single suvorexant doses were generally well tolerated in healthy subjects when co-administered with/without a CYP3A inhibitor/inducer.



The authors would like to thank Xiaodong Li for serving as a statistician and Hong Sun for serving as a clinical monitor during these trials. Christopher Lines, PhD, and Tamara Cabalu, PhD, of Merck & Co., Inc., Kenilworth, NJ, USA provided comments and edits on a draft of the manuscript. Medical writing support, under the direction of the authors, was provided by Adele Blair, PhD, of CMC AFFINITY, a division of McCann Health Medical Communications Ltd., Glasgow, UK, in accordance with Good Publication Practice (GPP3) guidelines.

Data availability

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA’s data sharing policy, including restrictions, is available at Requests for access to the clinical study data can be submitted through the EngageZone site or via email to

Compliance with Ethical Standards


These trials and medical writing support was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Conflict of interest

REW, JBM, KLY, WL, DP, EM, and MC 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. MPM-C was supported by National Institutes of Health Postdoctoral Training Grant No. T32GM008562. WKK has no disclosure to make.

Ethical approval

All procedures performed in studies involving human subjects 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.

Informed consent

Informed consent was obtained from all individual subjects included in the study.


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Copyright information

© Springer Nature Switzerland AG 2019
corrected publication 2019

Authors and Affiliations

  • Rebecca E. Wrishko
    • 1
  • Jacqueline B. McCrea
    • 1
    Email author
  • Ka Lai Yee
    • 1
  • Wen Liu
    • 1
  • Deborah Panebianco
    • 1
  • Eric Mangin
    • 1
  • Manu Chakravarthy
    • 1
  • Maria P. Martinez-Cantarin
    • 2
  • Walter K. Kraft
    • 2
  1. 1.Merck & Co., Inc.KenilworthUSA
  2. 2.Department of Pharmacology and Experimental TherapeuticsThomas Jefferson UniversityPhiladelphiaUSA

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