Pharmacokinetics and Pharmacodynamics of Orally Administered Ruxolitinib (INCB018424 Phosphate) in Renal and Hepatic Impairment Patients
Pharmacokinetics and Pharmacodynamics of Orally Administered Ruxolitinib (INCB018424 Phosphate) in Renal and Hepatic Impairment Patients
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DOI：
10.1002/cpdd.77
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发表时间：
2014-01-01
影响因子：
2
通讯作者：
Yeleswaram, Swamy
中科院分区：
文献类型：
--
作者：
Chen, Xuejun;Shi, Jack G.;Yeleswaram, Swamy
肝和肾损害的研究是用Ruxolitinib进行的，Ruxolitinib是一种JAK1&2抑制剂，主要通过代谢清除。这两项研究都是开放标签的单剂量研究。在轻度、中度和重度肝损害患者中，鲁索利替尼曲线下面积(AUC)分别比健康受试者增加87%、28%和65%，而鲁索利替尼的暴露与肝损害的程度无关。药效学(PD)数据与鲁索利替尼的药代动力学(PK)相一致。肾脏损伤研究显示了一个令人惊讶的发现。虽然鲁索利替尼PK在不同程度的肾损害中没有变化，但PD显示出随着肾损害严重程度的增加而增加的药理活性。对代谢物暴露的分析表明，活性代谢物有助于观察到PD活性的增加。透析液中Ruxolitinib的回收率可忽略不计。对于有任何肝损害或中、重度肾损害的患者，如果他们的血小板计数在100×10(9)/L到150×10(9)/L之间，鲁索利替尼的起始量应降至10 mg，每日2次。透析者应根据血小板计数开始单次剂量15或20 mg，仅在透析当天给药。
Hepatic and renal impairment studies were conducted with ruxolitinib, a JAK1&2 inhibitor that is cleared predominantly by metabolism. Both studies were open label, single-dose studies. Ruxolitinib area under the curve (AUC) was increased by 87%, 28%, and 65%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to healthy subjects with no correlation between exposure of ruxolitinib and the degree of hepatic impairment. The pharmacodynamics (PD) data were consistent with ruxolitinib pharmacokinetics (PK). The renal impairment study showed a surprising finding. While there was no change in ruxolitinib PK with varying degrees of renal impairment, the PD showed increasing pharmacological activity with increased severity of renal impairment. Analysis of the metabolite exposures revealed that active metabolites contributed to the observed incremental increase in PD activity. The recovery of ruxolitinib in dialysate was negligible. The starting dose of ruxolitinib in subjects with any hepatic impairment or moderate or severe renal impairment should be decreased to 10 mg twice daily (BID) if their platelet counts are between 100 x 10(9)/L and 150 x 10(9)/L. Subjects on dialysis should initiate dosing with a single dose of 15 or 20 mg, based on platelet counts, with dosing only on the days of dialysis.