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.