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

Abstract

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.

A review of the evidence base for utilizing Child-Pugh criteria for guiding dosing of anticancer drugs in patients with cancer and liver impairment

“…2021;10:99-109. 24 Participant number: 33 (normal hepatic function, n = 16; Child-Pugh class A, n = 9; Child-Pugh class B, n = 8) Patient characteristics: patients without cancer Lenvatinib For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma following 1 prior antiangiogenic therapy For the first-line treatment of patients with unresectable hepatocellular carcinoma Shumaker et al. J Clin Pharmacol .…”

Population pharmacokinetic and exposure‐response analyses of ivosidenib in patients with IDH1‐mutant advanced hematologic malignancies

“…A study dedicated to evaluating the single-dose PKs of ivosidenib 500 mg in patients with mild or moderate hepatic impairment (ClinicalTrials.gov NCT03282513) has been reported elsewhere, and showed that mild/moderate hepatic impairment did not lead to clinically relevant changes in ivosidenib exposure. 18 A substudy to evaluate the single-dose PKs of ivosidenib in patients with renal impairment was added to the phase I study (ClinicalTrials.gov NCT02074839).…”

“…As there was no clinically meaningful effect of mild hepatic or renal impairment on ivosidenib exposure, no dose adjustments are currently recommended for these target patient populations; however, these findings should be interpreted with caution as patients with severe renal impairment and moderate and severe hepatic impairment were under‐represented in this dataset. A study dedicated to evaluating the single‐dose PKs of ivosidenib 500 mg in patients with mild or moderate hepatic impairment (ClinicalTrials.gov NCT03282513) has been reported elsewhere, and showed that mild/moderate hepatic impairment did not lead to clinically relevant changes in ivosidenib exposure 18 . A substudy to evaluate the single‐dose PKs of ivosidenib in patients with renal impairment was added to the phase I study (ClinicalTrials.gov NCT02074839).…”

Preclinical Drug Metabolism, Pharmacokinetic, and Pharmacodynamic Profiles of Ivosidenib, an Inhibitor of Mutant Isocitrate Dehydrogenase 1 for Treatment of Isocitrate Dehydrogenase 1-Mutant Malignancies

“…Unbound fraction (f u ) of ivosidenib in human plasma was slightly higher at 10 µM (8.4%) compared with 0.2 µM (4.2%) and 1 µM (4.6%). In a study assessing the effect of hepatic impairment on the PK of ivosidenib, ex vivo mean unbound fractions at C max (~5 µM at 3 hours post dose) in two cohorts of healthy human participants with normal hepatic function were 2.48% and 1.75%, and f u decreased at lower concentrations (later sampling time points of 48 hours and 168 hours) (Fan et al, 2021). Binding affinities of ivosidenib to albumin and alpha-1 acid glycoprotein have not been determined.…”