An In Vitro and In Vivo Evaluation of the Effect of Relacorilant on the Activity of Cytochrome P450 Drug Metabolizing Enzymes

Relacorilant is a selective modulator of the glucocorticoid receptor in development for the treatment of several serious diseases. The widely used cocktail method was employed to assess relacorilant's effect on various cytochrome P450 (CYP) drug metabolizing enzymes in vitro and in vivo. Inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 as well as induction of CYP1A2, CYP2B6, and CYP3A4 were assessed in vitro (relacorilant concentrations up to 10 µM). A clinical study in healthy subjects (n = 27) evaluated the inhibition of CYP3A4, CYP2C8, and CYP2C9 in vivo by administering single doses of probe CYP substrates (midazolam, pioglitazone, and tolbutamide) alone and in combination with relacorilant (350 mg). Pharmacokinetic sampling was conducted, and safety was assessed throughout the study. Pharmacokinetic parameters were evaluated using 90% confidence intervals of the geometric least squares mean ratios of test (probe substrate with relacorilant) vs reference (probe substrate alone) using boundaries of 80% to 125%. In vitro, relacorilant inhibited CYP3A4, CYP2C8, and CYP2C9 but did not meaningfully affect the activity of the other CYP enzymes evaluated. Consistent with the in vitro data, relacorilant was shown to be a strong CYP3A inhibitor in vivo (>8‐fold increase in midazolam area under the concentration versus time curve from time zero to the last quantifiable concentration and area under the concentration versus time curve from time zero extrapolated to infinity). Coadministration of relacorilant with drugs highly dependent on CYP3A for clearance is expected to increase the concentrations of these drugs. Importantly, clinical evaluation of relacorilant showed no inhibition of CYP2C8 or CYP2C9 in vivo. Accordingly, drugs that are substrates of only CYP2C8 and/or CYP2C9 can be coadministered with relacorilant without dose adjustment.