Drug Interactions between gemfibrozil and seladelpar

GENERALLY AVOID: Concomitant administration with gemfibrozil may significantly increase the concentration and effects of seladelpar. The proposed mechanisms are inhibition of seladelpar's metabolism via CYP450 2C8 and 2C9, as well as, reduced renal tubular secretion via inhibition of the organic anion transporter 3 (OAT3) by gemfibrozil. Seladelpar is both a substrate of the OAT3 renal transporter and primarily metabolized in vitro by CYP450 2C9 and to a lesser extent by CYP450 2C8 and 3A4. In a clinical drug interaction study, the OAT3 inhibitor probenecid (500 mg four times daily) was given to healthy subjects on days 1 through 4, with a single dose of seladelpar (10 mg) administered on day 2. Seladelpar's systemic exposure (AUC) and maximum plasma concentration (Cmax) increased by 2- and 4.69-fold, respectively. A physiologically based pharmacokinetic (PBPK) model predicted that seladelpar's AUC would increase by 3.7-fold when coadministered with the strong CYP450 2C9 inhibitor sulfaphenazole. PBPK modeling was done with gemfibrozil using 2 different models, but neither took its effects on OAT3 into account and both treated it as a reversible CYP450 2C9 inhibitor. The models predicted an increase in seladelpar's AUC of 1.44- or 1.95-fold, depending on the model used. In vivo data are not available.

MANAGEMENT: Concomitant administration of seladelpar and gemfibrozil should generally be avoided as gemfibrozil is considered an OAT3 inhibitor as well as a potent CYP450 2C9 inhibitor.