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

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 favorable profile for insomnia treatment, including rapid onset of action and minimal next‐day residual effects.

Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia

“…Plasma concentration (ng/mL) Rat of dose). 30 These observations indicate that the main clearance mechanism of vornorexant is assumed to be metabolism in human and animals. Further investigation of the main clearance mechanism of vornorexant will be reported in a human mass balance study.…”

“…In human PK of vornorexant at 10 mg, the Vd/F and CL/F were reported to be 28.9 L and 10.5 L/h, respectively. 30 The small Vd of vornorexant, but not CL, accounts for the short t 1/2 in animals and humans. In addition, the BA was higher in dogs (58.0%) than rats (7.6%).…”

“…The concentration of vornorexant in CSF exceeded the in vitro effective concentration (rOX 1 R Kb: 0.20 ng/mL, rOX 2 R Kb: 0.36 ng/ mL) 29 immediately after administration, while the active metabolites had lower exposure in CSF and weaker pharmacological activity than the unchanged form (Table S6). In dogs and humans, 30 the unchanged form was the predominant component in plasma.…”

“…We found that vornorexant was rapidly absorbed ( T max <1 h) and eliminated with a short t 1/2 of approximately 1.0 and 2.5 h after the oral administration in rats and dogs, respectively. The predicted human t 1/2 , based on the preclinical data, was 0.9–2.0 h. Indeed, vornorexant exhibited the expected pharmacokinetics with rapid absorption ( T max <1 h) and short t 1/2 of 1.32–3.25 h at doses of 1–30 mg in healthy volunteers 30 . Vornorexant has exhibited the potent efficacy for inducing sleep onset and maintaining sleep, and also well tolerability in clinical studies in patients with insomnia 31 …”

“…The predicted human t 1/2 , based on the preclinical data, was 0.9-2.0 h. Indeed, vornorexant exhibited the expected pharmacokinetics with rapid absorption (T max <1 h) and short t 1/2 of 1.32-3.25 h at doses of 1-30 mg in healthy volunteers. 30 Vornorexant has exhibited the potent efficacy for inducing sleep onset and maintaining sleep, and also well tolerability in clinical studies in patients with insomnia. 31 Vornorexant seems to have desirable pharmacokinetics, with rapid absorption and relatively short half-life.…”