Evaluation of Pharmacokinetics and Safety of Imlunestrant in Participants with Hepatic Impairment.

The estrogen receptor (ER) is the key therapeutic target for ER-positive (ER+) breast cancer. Novel ER degraders may overcome resistance to available endocrine therapy while providing consistent oral bioavailability. Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) designed to deliver continuous ER target inhibition. A phase 1, open-label, 3-site study was conducted to characterize the pharmacokinetic (PK) profile of imlunestrant in individuals with varying degrees of hepatic impairment based on Child-Pugh and National Cancer Institute classifications. In this study, participants received a single oral dose of imlunestrant at either 200 or 400 mg in the fasted state, and the pharmacokinetics and safety were assessed in individuals with normal hepatic function and those with mild, moderate, or severe hepatic impairment. Based on Child-Pugh classification, there were no significant differences in the exposure profiles of imlunestrant in participants with mild hepatic impairment in comparison to participants with normal hepatic function. In participants with moderate and severe hepatic impairment, there were significant increases in imlunestrant AUC (but not Cmax) observed when compared with normal hepatic function (by 120% and 191% for AUC(0-tlast) and 122% and 206% for AUC(0-∞), respectively). Most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. Nausea and headache were the only TEAEs reported by more than one participant. Treatment-related adverse events were reported by two participants, one each from the moderate and severe hepatic impairment groups. This data will inform the recommendations for dosing patients with hepatic impairment under treatment with imlunestrant.