OBJECTIVE To investigate the pharmacokinetics of intravenous (IV) repinotan, a potent selective full serotonin (5-HT(1A)) receptor agonist, after administration of escalating doses/infusion rates to healthy volunteers with extensive or poor metaboliser phenotype, and to compare weight-adjusted (mg/kg) to fixed (mg/day) dosing regimens. SUBJECTS AND M ethods: The pharmacokinetic profile of IV repinotan was evaluated in healthy male volunteers. In eight studies, extensive metabolisers (EMs) and poor metabolisers (PMs) identified by sparteine phenotyping were given IV repinotan at doses of 5-100microg over 1 hour or 200-1000microg over 4 hours. In two additional studies of EMs and PMs, IV repinotan was administered as a weight-adjusted dose of 1 microg/kg/h for 24 hours. Repinotan plasma concentrations were measured for determination of non-compartmental pharmacokinetic parameters. RESULTS Sixty-five male subjects (54 EMs and 11 PMs) were valid for pharmacokinetic evaluation. During continuous IV infusion, a steady-state repinotan plasma level was reached within 4-5 hours in EMs, and the elimination half-life was 1 hour. Pharmacokinetics were linear in EMs across a wide range of doses (5-2250microg) and infusion rates (5-250 microg/h). Repinotan clearance was correlated with the log metabolic ratio (MR) of sparteine as an indicator for cytochrome P450 (CYP)2D6 phenotype, and subjects phenotyped as PMs had reduced clearance, resulting in longer elimination half-lives (up to a mean value of 11 hours) and increased peak plasma concentrations and area under the concentration-time curve values. Bodyweight was not a significant covariable for clearance and the interindividual variability in clearance was not reduced after normalisation to bodyweight. Repinotan was well tolerated at infusion rates up to 150 microg/h (EMs), and no clinically relevant safety issues were reported. CONCLUSIONS Repinotan demonstrates linear pharmacokinetics in EMs for CYP2D6, who constitute about 93% of the Caucasian population. Repinotan clearance is correlated with CYP2D6 phenotype and reduced in PMs. Bodyweight does not appear to be a major determinant of its pharmacokinetic variability and a bodyweight-adjusted dosing regimen is not warranted. Further studies should be performed in patients to investigate whether the tolerability profile of repinotan is comparable to that observed in healthy volunteers.