Effect of Mild to Moderate Hepatic Impairment on Valemetostat Pharmacokinetics: An Open-Label, Phase I Study.

Abstract

Valemetostat tosylate (valemetostat) is a dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1, approved in Japan for the treatment of relapsed/refractory peripheral T-cell lymphoma and adult T-cell leukemia/lymphoma. This Phase I, open-label study evaluated the pharmacokinetics and safety of a single 50-mg oral dose of valemetostat in participants with hepatic impairment (HI). In total, 24 participants were enrolled into 3 cohorts of mild HI (n = 8) and moderate HI (n = 8) according to the National Cancer Institute's Organ Dysfunction Working Group criteria, and matched healthy participants with normal hepatic function (HF; n = 8). In participants with mild and moderate HI, total valemetostat (bound + unbound) area under the concentration-time curve extrapolated to infinity was 23% lower (geometric mean ratio [GMR], 77.2% [90% confidence interval (CI), 44.0-135]) and 35% lower, (GMR, 64.8% [90% CI, 40.6-103]), respectively, and unbound valemetostat was 19% lower (GMR, 81.1% [90% CI, 47.4-139]) and 15% higher (GMR, 115% [90% CI, 75.5-176]), than in participants with normal HF. No treatment-related adverse events were reported. Based on the result of this trial, no dosing adjustments are recommended for patients with mild to moderate HI receiving valemetostat.