Effect of Hepatic Impairment on the Pharmacokinetics of Itacitinib

Itacitinib is a potent, selective JAK‐1 inhibitor currently in development for the treatment of chronic graft‐vs‐host‐disease in combination with corticosteroids. Itacitinib is primarily eliminated via cytochrome P450 3A metabolism with minimal renal elimination. The purpose of this open‐label study was to investigate the effect of hepatic impairment, as determined by Child‐Pugh grade, on itacitinib pharmacokinetics. All participants received a single 300‐mg dose of itacitinib orally in the fasted state. Blood samples were collected serially through 96 hours after dosing; 4 hours after dosing, an additional sample was collected for protein binding determination. Participants with moderate hepatic impairment (N = 8) had an approximate 2.5‐fold increase in total exposure (area under the plasma concentration–time curve from time 0 to infinity [AUC 0‐∞ ]) and an approximate 2‐fold increase in maximal exposure (C max ) compared to those with normal hepatic function (N = 8) (geometric mean ratio, 2.51 [90% confidence interval (CI), 1.54‐4.08] for AUC 0‐∞ and 1.95 [90%CI, 1.14‐3.35] for C max ). Participants with severe hepatic impairment (N = 6) had an approximate 4‐fold increase in total exposure (AUC 0‐∞ ) and an approximate 3.5‐fold increase in maximal exposure compared to participants with normal hepatic function (geometric mean ratio, 4.08 [90%CI, 2.41‐6.89] for AUC 0‐∞ and 3.48 [90%CI, 1.94‐6.23] for C max ). Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hepatic function, with average unbound fractions (percent free) of 25.7%, 31.5%, and 25.6%, respectively. There were no serious or fatal treatment‐related adverse events. The results of this study combined with exposure, efficacy, and safety data from the pivotal study in the relevant patient population will inform final dosing recommendations.