OBJECTIVE Repinotan hydrochloride (repinotan) is a selective, high-affinity, full serotonin receptor agonist at the 5-HT(1A) subtype that is undergoing clinical development in acute stroke. To investigate whether gender is an important covariable for repinotan pharmacokinetics, two studies were performed in subjects of different age and gender who had been phenotyped as extensive metabolisers for cytochrome P450 (CYP)2D6 using dextromethorphan as model substrate. METHODS Both studies were placebo-controlled, double-blind, randomised, parallel-group studies. Study I was conducted in six healthy young males, five healthy elderly males, and four healthy elderly females receiving a continuous intravenous (IV) infusion of repinotan 0.45 microg/kg/h or placebo for a duration of 12 hours. Study II was performed in healthy elderly male and female volunteers aged >/=65 years with 67 subjects receiving repinotan and 34 receiving placebo. Subjects received a 12-hour infusion of repinotan at doses of 0.1, 0.3, 0.5, 1.0, 2.0 or 3.0 microg/kg/h. RESULTS Following IV infusion, the steady-state plasma concentration (C(ss)) for repinotan was reached after 4-6 hours consistent with its half-life of 0.8-1.8 hours. In both male and female subjects, the volume of distribution at steady-state and plasma clearance (CL) were independent of dose, indicating linear pharmacokinetics and dose-proportionality for area under the concentration-time curve (AUC) and peak plasma concentration (C(max)) over the dose range of 0.1-3.0 microg/kg/h. Compared with elderly subjects, repinotan CL was unchanged in a subgroup of young subjects. The pooled evaluation of elderly subjects (n = 67) showed that gender had no influence on the pharmacokinetics of repinotan. The ratios male : female and their 90% CIs were: 0.91 (0.789, 1.052) for dose/bodyweight-normalised C(max) (C(max,norm)), 0.95 (0.808, 1.110) for half-life, 0.97 (0.900, 1.044) for V(ss,) and 1.11 (0.923, 1.336) for CL. CONCLUSIONS These results indicate that gender does not affect the pharmacokinetics of repinotan in healthy subjects whose age (>/=65 years) was representative of the target patient population for repinotan in acute stroke.