Effects of Cedirogant on the Pharmacokinetics of Sensitive Cytochrome P450 Probe Substrates.

Abstract

This study aimed to characterize the effects of cedirogant, an inverse agonist of retinoic acid-related orphan receptor gamma thymus (RORγt), on activities of cytochrome P450 (CYP) enzymes in healthy adults. Twenty study participants received a single oral dose of the modified Cooperstown 5+1 cocktail CYP probe drugs alone without cedirogant (Period 1, midazolam on Day 1 and other CYP substrates on Day 2), and again following once-daily dosing of 375 mg cedirogant (Period 2, cedirogant on Days 1-18, midazolam on Day 13, and other CYP substrates on Day 14). Blood samples and 12-hour urine samples were collected to measure the exposures of the CYP probe drugs and selected metabolites. The point estimates (90% confidence intervals) of the area under the plasma concentration-time curve from time 0 to infinity (AUC_inf) ratio with and without cedirogant co-administration were 0.370 (0.325-0.420) for midazolam (CYP3A), 1.161 (1.031-1.307) for caffeine (CYP1A2), and 0.788 (0.761-0.816) for S-Warfarin (CYP2C9). The estimated ratios of plasma metabolite/parent AUC ratio for omeprazole (CYP2C19) and parent/metabolite molar urine recovery ratio for dextromethorphan (CYP2D6) with versus without cedirogant co-administration were 2.115 (1.813-2.467) and 0.951 (0.802-1.128), respectively. Based on these findings, once-daily administration of 375-mg cedirogant showed moderate induction of CYP3A and CYP2C19, a weak effect on CYP2C9, and no clinically relevant effects on CYP1A2 or CYP2D6.