Evaluation of the pharmacokinetics of enasidenib in patients with hepatic impairment.

BACKGROUND: Enasidenib, an isocitrate dehydrogenase-2 (IDH2) inhibitor, is indicated for adult patients with relapsed/refractory acute myeloid leukemia (AML) with an IDH2 mutation. This study evaluated the pharmacokinetics (PK) and safety of enasidenib in subjects with hepatic impairment (HI). METHODS: A multicenter, open-label study assessed the PK of a single 100 mg oral dose of enasidenib in subjects with mild (n = 8), moderate (n = 8), and severe (n = 8) HI (Child-Pugh classification) and matched healthy controls (n = 16). Plasma concentrations of enasidenib and its active metabolite, AGI-16,903, were analyzed, and PK parameters were compared between HI groups and healthy controls. RESULTS: Following a single oral dose, enasidenib exposure (AUC0-∞) was comparable across all groups, with geometric mean ratios (GMRs) of 97.7%, 96.7%, and 87.4% for mild, moderate, and severe HI versus healthy controls, respectively. Cmax values showed similar trends, with GMRs of 119%, 85.7%, and 86.4% for mild, moderate, and severe HI, respectively. AGI-16,903 exposure decreased with increasing HI severity, with GMRs for AUC0-∞ of 86.3%, 65.0%, and 61.1% for mild, moderate, and severe HI, respectively. CONCLUSION: HI did not significantly alter PK of enasidenib. While AGI-16,903 exposure decreased with increasing HI severity, the impact was not deemed clinically relevant. Taken together, the results of this study support the conclusion that no dose adjustment is warranted for subjects with mild, moderate, or severe HI.