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Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of a Single Dose of Oral Ivosidenib in Otherwise Healthy Participants
Author(s) -
Fan Bin,
Dai David,
Cohen Marvin,
Xu Huansheng,
Yin Feng,
Nagaraja Raj,
Mobilia Michelle,
Almon Caroline,
Basile Frank G.,
Yang Hua
Publication year - 2021
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.821
Subject(s) - medicine , cmax , pharmacokinetics , adverse effect , tolerability , discontinuation , confidence interval , clearance , gastroenterology , urology
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 (C max ) 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 C max 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 C max 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.