Single- and Multiple-Dose Pharmacokinetics and Tolerability of Gepirone Extended-Release

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To determine the single- and multiple-dose pharmacokinetic profile of gepirone extended-release (ER) in healthy individuals. 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 l-pyrimidinyl-(2-pipera-zine) [1-PP] metabolite prior to the first dose and other intervals on the first and last treatment days. Pharmacokinetic parameters included peak plasma level (Cmax), time to peak plasma level (tmax), and area under the concentration-time curve (AUC). 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 (Cmin) 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 pharmaco-kinetic profile was observed for the 1-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. 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.