LAUSR

Abstract Miricorilant is a novel selective glucocorticoid receptor (GR) modulator with mixed agonist/antagonist effects at the GR and modest antagonism at the mineralocorticoid receptor that is being developed for the treatment of metabolic dysfunction‐associated steatohepatitis. Its overall pharmacokinetic characteristics were assessed, including its disposition (absorption, distribution, metabolism, and elimination [ADME]) and drug–drug interaction (DDI) potential. In vitro, miricorilant (1) demonstrated >99% plasma protein binding in mice, rats, monkeys, and humans, (2) was a modest inhibitor of CYP3A4, CYP2C8, CYP2C9, UGT1A1, and a strong inhibitor of BCRP, (3) was predominantly metabolized by CYP2C19 (≈94%), and (4) showed no induction potential for CYP1A2 and CYP2B6, but showed a concentration‐dependent induction of CYP3A4 (6.5‐fold) in 1 out of 3 donors tested. In a tissue distribution study in mice, miricorilant was distributed with high levels of radioactivity present in several tissues, including the liver. In animal and human ADME studies, the majority of total radioactivity was recovered in feces (>78%) versus urine (<5%), suggesting hepatic elimination with minor contribution of renal elimination. In phase 1 clinical studies in healthy subjects, miricorilant showed an approximately dose‐proportional increase in systemic exposure in the dose range 100–900 mg with an elimination half‐life of ≈20 h. In clinical DDI studies at the total plasma concentrations evaluated, miricorilant was a strong inhibitor of CYP2C8 and a moderate inhibitor of BCRP with no meaningful inhibition of CYP2C9, CYP3A4, or UGT1A1, and a moderately sensitive substrate of CYP2C19. Miricorilant was safe and well‐tolerated in the phase 1 studies.