Single- and multiple-dose pharmacokinetics and tolerability of gepirone extended-release

Objective: To determine the single- and multiple-dose pharmacokinetic profile of gepirone extended-release (ER) in healthy individuals. Methods: The single- and multiple-dose pharmacokinetics of gepirone-ER were investigated in three randomised, placebo-controlled studies of 115 healthy subjects. Dosages ranged from 10 to 75 mg/day for 6 days (study 1), 20 mg/day for 7 days (study 2), and 120 mg/day for 7 days (study 3). Blood samples were obtained to measure plasma levels of gepirone and the 1-pyrimidinyl-(2-piperazine) [I-PP] metabolite prior to the first dose and other intervals on the first and last treatment days. Pharmacokinetic parameters included peak plasma level (C-max), time to peak plasma level (t(max), and area under the concentration-time curve (AUC). Results: In single-dose studies, peak gepirone-ER plasma concentrations were reached in approximately 4 to 5 hours and slowly declined over the next 20 hours. Steady-state plasma gepirone concentrations were reached by day 2 during multiple-dose studies; Cmax, minimum trough plasma concentration (C-min) and AUC were dose proportional. Greater fluctuations in plasma concentrations were observed with gepirone solution than with gepirone-ER. The AUC for gepirone-ER was approximately 80% of that for gepirone solution. A similar pharmacokinetic profile was observed for the I-PP metabolite. Gepirone-ER was generally well tolerated at all doses in all age groups except for 120 mg/day. The incidence of adverse events, including headache, dizziness and nausea, tended to be higher in gepirone-ER than in placebo recipients. Conclusions: Gepirone and 1-PP exhibited linear pharmacokinetic profiles. Peak/trough fluctuations in plasma gepirone concentrations were reduced by gepirone-ER, while total exposure to drug (AUC) was maintained. Overall, gepirone-ER was well tolerated. As a result of lower peak plasma levels, gepirone-ER may be expected to reduce the incidence of adverse events compared with gepirone immediate-release and thus has the potential to improve response.