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 [(14)C]
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 (KI = 12 μM, kinact = 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.