Ketoconazole Inhibition of Gepirone Biotransformation and Clearance: In Vitro and Clinical Studies

Gepirone, an antidepressant drug, is biotransformed into two principal metabolites [1-(2-pyrimidinyl)-piperazine (1-PP) and 3'-OH-gepirone] primarily by CYP3A enzymes. Metabolism of gepirone in the presence of ketoconazole, a potent inhibitor of human CYP3A activity, was studied in vitro in human liver microsomes. The clinical pharmacokinetic interaction of ketoconazole (as a maximal chemical inhibitor of CYP3A isoforms) with single doses of gepirone was evaluated in a Phase 1 study in human volunteers (N = 24). In vitro coincubation of gepirone with increasing concentrations of ketoconazole produced extensive inhibition of 1-PP and 3'-OH-gepirone formation, with IC₅₀ values in the range of 0.026 µM to 0.162 µM. These inhibitory values are substantially lower than clinically encountered systemic concentrations of ketoconazole, thereby predicting extensive in vivo increases in gepirone exposure when coadministered with ketoconazole. In the clinical pharmacokinetic study, ketoconazole produced large increases in gepirone exposure by factors of 5.92- to 7.80-fold. Appearance of 1-PP in the systemic circulation decreased by factors of 0.56 to 0.97, while appearance of 3'-OH-gepirone increased by 1.70- to 2.43-fold. The clinical findings are consistent with the in vitro results, and underlie the labeling recommendation that gepirone not be coadministered with "strong" CYP3A inhibitors.