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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

Abstract

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.

Methods

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.

Results

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.

Conclusions

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.

Notes

Acknowledgements

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 http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to dataaccess@merck.com.

Compliance with Ethical Standards

Funding

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.

References

  1. 1.
    Winrow CJ, Renger JJ. Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br J Pharmacol. 2014;171(2):283–93.CrossRefGoogle Scholar
  2. 2.
    Roecker AJ, Coleman PJ. Orexin receptor antagonists: medicinal chemistry and therapeutic potential. Curr Top Med Chem. 2008;8(11):977–87.CrossRefGoogle Scholar
  3. 3.
    Coleman PJ, Gotter AL, Herring WJ, Winrow CJ, Renger JJ. The discovery of suvorexant, the first orexin receptor drug for insomnia. Annu Rev Pharmacol Toxicol. 2017;57:509–33.CrossRefGoogle Scholar
  4. 4.
    Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ. International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacol Rev. 2012;64(3):389–420.CrossRefGoogle Scholar
  5. 5.
    Yoshida Y, Fujiki N, Nakajima T, Ripley B, Matsumura H, Yoneda H, et al. Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities. Eur J Neurosci. 2001;14(7):1075–81.CrossRefGoogle Scholar
  6. 6.
    Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2011;51:243–66.CrossRefGoogle Scholar
  7. 7.
    Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573–85.CrossRefGoogle Scholar
  8. 8.
    Merck Sharp & Dohme Corp. Belsomra (suvorexant) Package Insert. 2014. http://www.merck.com/product/usa/pi_circulars/b/belsomra/belsomra_pi.pdf. Accessed 26 June 2018.
  9. 9.
    Kawabe K, Horiuchi F, Ochi M, Nishimoto K, Ueno SI, Oka Y. Suvorexant for the treatment of insomnia in adolescents. J Child Adolesc Psychopharmacol. 2017;27:792–5.CrossRefGoogle Scholar
  10. 10.
    Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology. 2012;79(23):2265–74.CrossRefGoogle Scholar
  11. 11.
    Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, et al. Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry. 2016;79(2):136–48.CrossRefGoogle Scholar
  12. 12.
    Herring WJ, Connor KM, Snyder E, Snavely DB, Zhang Y, Hutzelmann J, et al. Suvorexant in elderly patients with insomnia: pooled analyses of data from Phase III randomized controlled clinical trials. Am J Geriatr Psychiatry. 2017;25(7):791–802.CrossRefGoogle Scholar
  13. 13.
    Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a Phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014;13(5):461–71.CrossRefGoogle Scholar
  14. 14.
    Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X, et al. Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep. 2013;36(2):259–67.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Vermeeren A, Vuurman E, Bautmans A, Li X, Vets E, Lewis N, et al. Suvorexant, a dual orexin receptor antagonist, does not impair next day driving performance in healthy elderly subjects. Sleep. 2012;35(Abstract Supplement):pA226 (Abstract 0670).Google Scholar
  16. 16.
    Vermeeren A, Vuurman E, Van Oers A, Van Leeuwen C, Jongen S, Bautmans A, et al. Effects of suvorexant, an orexin receptor antagonist on next day driving performance in healthy non-elderly subjects. Neuropsychopharmacology. 2012;38(Suppl 1):S320–1.Google Scholar
  17. 17.
    U.S. Food and Drug Administration. Clinical Drug Interaction Studies — Study Design, Data Analysis, and Clinical Implications Guidance for Industry DRAFT GUIDANCE. 2017. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. Accessed 28 June 2018.
  18. 18.
    RxList. Ambien (zolpidem) Package Insert. 2004. https://www.rxlist.com/ambien-drug/patient-images-side-effects.htm. Accessed 29 June 2018.
  19. 19.
    Sunovion Pharmaceuticals Inc. Lunesta [package insert]. 2014. http://www.lunesta.com/PostedApprovedLabelingText.pdf. Accessed 29 June 2018.
  20. 20.
    Cui D, Cabalu T, Yee KL, Small J, Li X, Liu B, et al. In vitro and in vivo characterisation of the metabolism and disposition of suvorexant in humans. Xenobiotica. 2016;46(10):882–95.CrossRefGoogle Scholar
  21. 21.
    U.S. Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 2018. https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm. Accessed 3 July 2018.
  22. 22.
    Greenblatt DJ, Wright CE, von Moltke LL, Harmatz JS, Ehrenberg BL, Harrel LM, et al. Ketoconazole inhibition of triazolam and alprazolam clearance: differential kinetic and dynamic consequences. Clin Pharmacol Ther. 1998;64(3):237–47.CrossRefGoogle Scholar
  23. 23.
    Sutton D, Butler AM, Nadin L, Murray M. Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther. 1997;282(1):294–300.PubMedGoogle Scholar
  24. 24.
    Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT. Pharmacokinetic interactions with rifampicin : clinical relevance. Clin Pharmacokinet. 2003;42(9):819–50.CrossRefGoogle Scholar
  25. 25.
    Villikka K, Kivisto KT, Backman JT, Olkkola KT, Neuvonen PJ. Triazolam is ineffective in patients taking rifampin. Clin Pharmacol Ther. 1997;61(1):8–14.CrossRefGoogle Scholar
  26. 26.
    Villikka K, Kivisto KT, Luurila H, Neuvonen PJ. Rifampin reduces plasma concentrations and effects of zolpidem. Clin Pharmacol Ther. 1997;62(6):629–34.CrossRefGoogle Scholar
  27. 27.
    Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther. 1996;59(1):7–13.CrossRefGoogle Scholar
  28. 28.
    Stoch SA, Friedman E, Maes A, Yee K, Xu Y, Larson P, et al. Effect of different durations of ketoconazole dosing on the single-dose pharmacokinetics of midazolam: shortening the paradigm. J Clin Pharmacol. 2009;49(4):398–406.CrossRefGoogle Scholar
  29. 29.
    Friedman EJ, Fraser IP, Wang Y-H, Bergman AJ, Li C-C, Larson PJ, et al. Effect of different durations and formulations of diltiazem on the single-dose pharmacokinetics of midazolam: how long do we go? J Clin Pharmacol. 2011;51(11):1561–70.CrossRefGoogle Scholar
  30. 30.
    Sun H, Kennedy WD, Lewis N, Laethem T, Tee K, Li X, et al. The single dose pharmacokinetic (PK) and pharmacodynamic (PD) profiles of suvorexant (MK-4305), a dual orexin receptor antagonist, in healthy male subjects. Sleep Biol Rhythms. 2011;9(4):332 (Abstract).Google Scholar
  31. 31.
    Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994;55(5):481–5.CrossRefGoogle Scholar
  32. 32.
    Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994;56(6 Pt 1):601–7.CrossRefGoogle Scholar
  33. 33.
    Kronbach T, Mathys D, Umeno M, Gonzalez FJ, Meyer UA. Oxidation of midazolam and triazolam by human liver cytochrom P450IIIA4. Mol Pharmacol. 1989;36:89–96.PubMedGoogle Scholar
  34. 34.
    Breidinger SA, Simpson RC, Mangin E, Woolf EJ. Determination of suvorexant in human plasma using 96-well liquid-liquid extraction and HPLC with tandem mass spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2015;1002:254–9.CrossRefGoogle Scholar
  35. 35.
    Yee KL, McCrea J, Panebianco D, Liu W, Lewis N, Cabalu T, et al. Safety, tolerability, and pharmacokinetics of suvorexant: a randomized rising-dose trial in healthy men. Clin Drug Invest. 2018;38(7):631–8.CrossRefGoogle Scholar
  36. 36.
    Drugs.com. Sonata (zaleplon) Package Insert. 2004. https://www.drugs.com/sonata.html. Accessed 3 July 2018.

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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