Pharmacokinetics of gepirone in subjects with normal renal function and in patients with chronic renal dysfunction

Objective: To compare the pharmacokinetic profiles of gepirone and its main metabolites, 1-(2-pyrimidinyl)-piperazine (1-PP) and the 3'-hydroxy derivative (3'-OH-gepirone) after a single oral dose of gepirone extended-release (gepirone-ER) in subjects with normal renal function and in patients with various levels of renal dysfunction. Design: Open-label, parallel-group, single oral dose pharmacokinetic study. Participants: 37 subjects, aged 35 to 65 years with normal renal function (n = 9) or mild (n = 9), moderate (n = 9) or severe (n = 10) renal impairment Methods: All subjects received a single oral dose of gepirone-ER (two 20mg tablets) under fasting conditions. Participants were matched with regard to age and body mass index. Serial blood samples were drawn over 96 hours to measure plasma concentrations of gepirone, 1-PP and 3'-OH-gepirone. Urine was collected to assess the excretion of gepirone and its metabolites. Results: The exposure [area under the plasma concentration-time curve (AUC), maximum plasma concentration (C-max)] to gepirone, 1-PP and 3'-OH-gepirone increased with decreasing renal function. The AUC of gepirone and its metabolites was greatest in patients with the severest renal dysfunction. No difference was observed in the elimination half-life (t(1)/(2)) of gepirone, but the t(1)/(2) of the metabolites was longer in patients with severe dysfunction than in those with normal renal function. Renal clearance of gepirone, I-PP and 3'-OH-gepirone was higher in those with normal function than in patients with severe dysfunction. Adverse events (18) occurred more frequently only in subjects with severe renal impairment, Conclusions: Gepirone-ER was generally well tolerated among patients with varying degrees of renal impairment. Exposure to gepirone and its metabolites was increased by renal impairment, especially in subjects with severe dysfunction. Therefore, caution should be used when selecting the dose of gepirone in patients with severe renal impairment.