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

ABSTRACT 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 OX 1 and OX 2 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 OX 2 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 OX 2 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 OX 1 receptor by vornorexant was higher than that of the OX 2 receptor. The estimated human OX 1 and OX 2 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 OX 2 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.