Incyte Corporation, Wilmington, Delaware, USA.
GlaxoSmithKline Research & Development, Wilmington, Delaware, USA.
J Clin Pharmacol. 2021 Jul;61(7):954-960. doi: 10.1002/jcph.1814. Epub 2021 Jan 28.
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 ]) and an approximate 2-fold increase in maximal exposure (C ) compared to those with normal hepatic function (N = 8) (geometric mean ratio, 2.51 [90% confidence interval (CI), 1.54-4.08] for AUC and 1.95 [90%CI, 1.14-3.35] for C ). Participants with severe hepatic impairment (N = 6) had an approximate 4-fold increase in total exposure (AUC ) 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 and 3.48 [90%CI, 1.94-6.23] for C ). 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.
伊他替尼是一种强效、选择性的 JAK1 抑制剂，目前正在开发用于联合皮质类固醇治疗慢性移植物抗宿主病。伊他替尼主要通过细胞色素 P450 3A 代谢消除，肾脏消除很少。本开放性研究的目的是研究肝损伤（根据 Child-Pugh 分级确定）对伊他替尼药代动力学的影响。所有参与者均空腹单次口服 300mg 伊他替尼。给药后通过 96 小时连续采集血样；给药后 4 小时，额外采集一份样本用于测定蛋白结合率。中重度肝损伤患者（N=8）的总暴露量（从 0 到无穷时的血浆浓度-时间曲线下面积[AUC ]）约增加 2.5 倍，最大暴露量（C ）约增加 2 倍，与肝功能正常患者（N=8）相比（几何均数比，2.51[90%置信区间（CI），1.54-4.08] AUC ；1.95[90%CI，1.14-3.35] C ）。重度肝损伤患者（N=6）的总暴露量（AUC ）约增加 4 倍，最大暴露量约增加 3.5 倍，与肝功能正常患者相比（几何均数比，4.08[90%CI，2.41-6.89] AUC ；3.48[90%CI，1.94-6.23] C ）。中重度肝损伤患者与肝功能正常患者的蛋白结合率相似，平均未结合分数（游离百分比）分别为 25.7%、31.5%和 25.6%。无严重或致命的治疗相关不良事件。本研究结果结合相关患者人群中关键性研究的暴露量、疗效和安全性数据，将为最终给药建议提供信息。
