Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of a Single Dose of Oral Ivosidenib in Otherwise Healthy Participants.

Ivosidenib, a small-molecule inhibitor of mutant isocitrate dehydrogenase 1, is primarily cleared by hepatic metabolism. This open-label study investigated the impact of hepatic impairment on ivosidenib pharmacokinetics (ClinicalTrials.gov: NCT03282513). Otherwise healthy participants with mild (n = 9) or moderate (n = 8) hepatic impairment (Child-Pugh score) and matched participants with normal hepatic function (n = 16) received 1 oral dose of 500-mg ivosidenib. Mild hepatic impairment had a negligible effect on total ivosidenib plasma exposure, with geometric mean ratios (90% confidence interval [CI]) of 0.933 (0.715-1.22) for maximum concentration (Cmax ) and 0.847 (0.624-1.15) for area under the plasma concentration-time curve (AUC) in participants with mild hepatic impairment versus matched controls. Moderate hepatic impairment reduced total ivosidenib exposure by 28% to 44%, with geometric mean ratios (90%CI) of 0.565 (0.419-0.763) for Cmax and 0.716 (0.479-1.07) for AUC, although the 90%CI for AUC included 1.00. The ivosidenib unbound fraction was concentration dependent and higher in participants with mild/moderate hepatic impairment compared with matched controls. There was no apparent trend to increasing unbound Cmax with increased hepatic impairment severity. A single 500-mg ivosidenib dose was well tolerated, with no serious or severe adverse events and no adverse events leading to discontinuation. We conclude that mild/moderate hepatic impairment did not lead to clinically relevant changes in ivosidenib exposure following a single 500-mg dose.