Pharmacokinetics, mass balance and metabolic profiling of resmetirom in healthy subjects and nonclinical metabolism and disposition

(200/200 words)Resmetirom is a liver-directed, thyroid hormone receptor-β (THR-β)-selective agonist approved for treatment of adults with metabolic dysfunction-associated steatohepatitis (MASH) and moderate-to-advanced liver fibrosis. Disposition in rats and dogs was qualitatively similar to that observed in humans, with high concentrations observed in liver, kidney, and cecum. The primary circulating metabolite, MGL-3623 (M1), was disproportionate in humans and formed predominantly via CYP2C8. Resmetirom exhibited >99% plasma protein binding in all species and was a substrate for BCRP, OSTα/β, OATP1B1/B3, and, to a lesser extent, MDR1.A [14C]resmetirom mass balance study in healthy men pre-dosed with 100 mg/d resmetirom (steady-state) demonstrated plasma pharmacokinetics of total radioactivity aligned with unlabelled resmetirom and MGL-3623, with Cmax reached within 3–4 h. Radioactivity was largely confined to plasma vs whole blood, with parent compound the predominant radiolabelled species and MGL-3623 the major metabolite. Total recovery was 91.0% (excretion: 67.4% faecal, 23.6% urinary); in excreta, resmetirom was a minor component and no single metabolite exceeded 10% of dose. Resmetirom inhibited CYP2C8 and weakly induced CYP2B6 and CYP3A4 in vitro.These findings demonstrate the consistent metabolic profile and favourable hepatic disposition of resmetirom across species, supporting its pharmacokinetic properties in humans for treatment of MASH.