Safety and Pharmacokinetics of High‐Dose TAS‐303 in Healthy Japanese Volunteers: A Single‐Center, Single‐Blind, Randomized, Placebo‐Controlled, Parallel‐Group, Multiple‐Ascending‐Dose Study

Preclinical data of TAS‐303 (4‐piperidinyl 2,2‐diphenyl‐2‐[propoxy‐1,1,2,2,3,3,3‐d(7)] acetate hydrochloride), a noradrenaline reuptake inhibitor, show that it increases urethral contraction in rats and may therefore benefit stress urinary incontinence patients. In this single‐blind, randomized, placebo‐controlled, parallel‐group, multiple‐ascending‐dose phase 1 study, we evaluated the safety and tolerability of once‐daily TAS‐303 8, 10, 12, 15, or 18 mg administered for 16 days in healthy subjects. In addition, we investigated the pharmacokinetics and inhibitory effect of TAS‐303 on hepatic cytochrome P450 (CYP) 3A activity. Rates of adverse events, adverse drug reactions, and pharmacokinetic parameters of TAS‐303 were evaluated. Fifty subjects were randomized: 7 subjects each were assigned to receive TAS‐303 8‐18 mg, and 3 subjects each were assigned to receive placebo at each dose. The overall incidences of adverse events and adverse drug reactions in all subjects administered TAS‐303 (n = 35) was 25.7% and 2.9%, respectively, and those for the placebo groups (n = 15) were 46.7% and 0%, respectively. No deaths or serious adverse events occurred. TAS‐303 displayed a dose‐proportional pharmacokinetic profile across doses of 8‐18 mg over the 16‐day multiple administration period, and TAS‐303 might inhibit hepatic CYP3A activity within this dose range. TAS‐303 at a dose of 8‐18 mg was confirmed to be safe and tolerable.