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

Abstract

AbstractThe 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.