Estimation of the Orexin Receptor Occupancy From Human Plasma Pharmacokinetics of Vornorexant, a Novel Dual Orexin 1/2 Receptor Antagonist for the Treatment of Insomnia

Vornorexant is a novel dual orexin receptor antagonist (DORA) for the treatment of insomnia with a short elimination half-life. Estimation of the human orexin receptor occupancy can provide insight into the duration of the sleep-promoting effect of DORAs. Herein, we developed a pharmacokinetic-receptor occupancy (PK/RO) model for OX₁ and OX₂ receptors in rats and estimated their receptor occupancy in humans based on the human plasma concentrations after oral administration of vornorexant. The estimated occupancy of the human OX₂ receptor, which is primarily involved in sleep induction, exceeded 70% at 30 min after dosing of therapeutic doses of 5 and 10 mg. The human OX₂ receptor occupancy at 6 h post-dose of 5 and 10 mg was estimated to be approximately 50% and 60%, respectively, comparable to the occupancy necessary to exert sleep-promoting effects in rats. Occupancy of the human OX₁ receptor by vornorexant was higher than that of the OX₂ receptor. The estimated human OX₁ and OX₂ receptor occupancy decreased with short half-lives depending on the plasma concentration. These results suggest that vornorexant exerts rapid sleep-promoting effects and maintains sleep for at least 6 h, and these estimations of the OX₂ receptor occupancy could support the clinical results. Vornorexant may have a favorable PK/RO profile for rapid sleep onset and sufficient sleep maintenance with minimal next-day residual effects in humans.