Clinical Pharmacokinetic Studies of Enzalutamide.
Clinical Pharmacokinetic Studies of Enzalutamide.
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DOI：
10.1007/s40262-015-0271-5
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发表时间：
2015-10
影响因子：
4.5
通讯作者：
Mordenti J
中科院分区：
文献类型：
--
作者：
Gibbons JA;Ouatas T;Krauwinkel W;Ohtsu Y;van der Walt JS;Beddo V;de Vries M;Mordenti J
口服Enzalutamide（160 mg，每日一次）已获批用于治疗转移性去势抵抗性前列腺癌（mCRPC）。本文描述了Enzalutamide及其活性代谢产物N-去甲基Enzalutamide的药代动力学。结果来自五项临床研究。在一项剂量递增研究（n = 140）中，Enzalutamide的半衰期为5.8天，在第28天达到稳态，蓄积为8.3倍，暴露量在30-360 mg/天范围内与剂量大致成比例，受试者间变异性≤ 30%。在一项质量平衡研究（n = 6）中，Enzalutamide主要通过肝脏代谢消除。肾脏排泄是Enzalutamide和N-去甲基Enzalutamide的不显著消除途径。在一项食物效应研究（n = 60）中，食物对Enzalutamide或N-去甲基Enzalutamide的血药浓度-时间曲线下面积（AUC）没有有意义的影响，在一项肝损害研究中，轻度（n = 6）或中度（n = 8）损害男性中enzalutamide + N-去甲基enzalutamide总和的AUC相似（Child-Pugh A级和B级）与肝功能正常男性（n = 14）。在一项III期试验中，对稳态给药前（谷）浓度（Ctrough）与总生存期（n = 1103）进行的剂量-效应分析显示，160 mg/天活性治疗Ctrough四分位数相对于安慰剂一致有益，Ctrough阈值与统计学显著性更佳缓解无关。Enzalutamide具有可预测的药代动力学，受试者间变异性较低。在与enzalutamide 160 mg/天固定口服剂量相关的浓度/暴露范围内，在患者中观察到相似的疗效。本文的在线版本（doi：10.1007/s40262-015-0271-5）包含补充材料，可供授权用户使用。
Oral enzalutamide (160 mg once daily) is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This article describes the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide. Results are reported from five clinical studies. In a dose-escalation study (n = 140), enzalutamide half-life was 5.8 days, steady state was achieved by day 28, accumulation was 8.3-fold, exposure was approximately dose proportional from 30–360 mg/day, and intersubject variability was ≤30 %. In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism. Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide. In a food-effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration–time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child–Pugh Class A and B) versus men with normal hepatic function (n = 14). In a phase III trial, an exposure-response analysis of steady-state predose (trough) concentrations (Ctrough) versus overall survival (n = 1103) showed that active treatment Ctrough quartiles for 160 mg/day were uniformly beneficial relative to placebo, and no threshold of Ctrough was associated with a statistically significant better response. Enzalutamide has predictable pharmacokinetics, with low intersubject variability. Similar efficacy was observed in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day. The online version of this article (doi:10.1007/s40262-015-0271-5) contains supplementary material, which is available to authorized users.