Pharmacokinetics, pharmacodynamics and safety profile of the dual orexin receptor antagonist vornorexant/TS-142 in healthy Japanese participants following single/multiple dosing: Randomized, double-blind, placebo-controlled phase-1 studies.

The pharmacokinetics, pharmacodynamics and safety profile of vornorexant were investigated in healthy Japanese participants in three double-blind studies: a single ascending dose of 1-30 mg (Study 101; n = 6) and multiple ascending doses of 10-30 mg (Study 102; n = 6). Study 202 consisted of two steps: an open-label, 20 mg repeated-dose in non-elderly individuals (Step 1; n = 12) and a double-blind, 20 mg repeated-dose in elderly individuals (Step 2; n = 8/3 for vornorexant/placebo). Vornorexant was rapidly absorbed and eliminated under fasting conditions, with a time to maximum plasma concentration of 0.500-3.00 h (range) and elimination half-life of 1.32-3.25 h. The area under the plasma concentration-time curve (AUC) of vornorexant increased proportionally with dose increments. Sleepiness-related pharmacodynamic outcome changes (Karolinska sleepiness scale, digit symbol substitution test and psychomotor vigilance task) were generally increased with dose increments at 1 and 4 h post-dose, whereas no consistent dose-related changes were detected the next morning. Food intake did not affect the maximum observed plasma concentration of vornorexant but increased the AUC0-inf . Exposure in elderly individuals was generally comparable to that in non-elderly individuals. Altogether, vornorexant may have a favourable profile for insomnia treatment, including rapid onset of action and minimal next-day residual effects.