In vitro and in vivo characterisation of the metabolism and disposition of suvorexant in humans

Abstract

1. Suvorexant (MK-4305, Belsomra®) is a first-in-class dual orexin receptor antagonist approved in the USA and Japan for the treatment of insomnia. The current studies describe suvorexant’s absorption, disposition and potential for CYP-mediated drug interactions in humans.

2. Following single oral administration of [¹⁴C]suvorexant to healthy human subjects, 90% of the radioactivity was recovered (66% in faeces, 23% in urine), primarily as oxidative metabolites.

3. In plasma, suvorexant and M9 were predominant, accounting for 30 and 37% of the total radioactivity, respectively. Metabolite M17 became more prominent (approaching 10%) following multiple daily doses of unlabelled suvorexant. M9 and M17 are not expected to contribute to the pharmacological activity of suvorexant due to reduced orexin receptor binding affinity and limited brain penetration.

4. CYP3A was determined to be the predominant enzyme mediating suvorexant oxidation. In vitro, suvorexant demonstrated reversible inhibition of CYP3A4 and 2C19 (IC₅₀ ∼ 4–5 μM), and weak time-dependent inhibition of CYP3A4 (K_I = 12 μM, k_inact = 0.14 min⁻¹). Suvorexant was also a weak inducer of CYP3A4, 1A2 and 2B6. Given the low plasma concentrations at clinical doses, suvorexant was not anticipated to cause significant drug interactions via inhibition and/or induction of major CYPs in vivo.

• Human ADME
• insomnia
• in vitro metabolism
• MK-4305
• orexin
• suvorexant

Acknowledgements

The authors would like to thank Rebecca Wrishko and Zhoupeng Zhang, Merck & Co., Inc, and Tom Baillie, University of Washington, for helpful discussions. The authors wish to acknowledge the transporter and bioanalysis groups in Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism of Merck & Co., Inc, Kenilworth, NJ for their support. Gina Rocco, PhD, and Michael Pellegrino, PhD, of Complete Medical Communications (CMC), Inc., Hackensack, NJ, provided medical writing support under the direction of the authors, funded by Merck & Co., Inc., Kenilworth, NJ.

Declaration of interest

Cui, Cabalu, B. Liu, Maciolek, Smith, Prueksaritanont, Small, Yee, McCrea, W. Liu, and Li were employees of Merck & Co., Inc and owned stock in Merck & Co., Inc at the time of this study.