Effect of the CYP3A Inhibitor Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Bortezomib in Patients With Advanced Solid Tumors: A Prospective, Multicenter, Open-Label, Randomized, Two-Way Crossover Drug-Drug Interaction Study
Effect of the CYP3A Inhibitor Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Bortezomib in Patients With Advanced Solid Tumors: A Prospective, Multicenter, Open-Label, Randomized, Two-Way Crossover Drug-Drug Interaction Study
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DOI：
10.1016/j.clinthera.2009.11.012
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发表时间：
2009-01-01
影响因子：
3.2
通讯作者：
Chatta, Gurkamal
中科院分区：
文献类型：
--
作者：
Venkatakrishnan, Karthik;Rader, Michael;Chatta, Gurkamal
背景资料：蛋白酶体抑制剂硼替佐米通过多种细胞色素P450（CYP 3A 4）酶进行氧化生物转化，CYP 3A 4被鉴定为部分但潜在重要的贡献者，基于体外药物代谢研究。目的：本研究的目的是评估伴随施用酮康唑对硼替佐米的药代动力学（PK）和药效学（PD）的影响。这是一项在晚期实体瘤患者中进行的前瞻性、多中心、开放标签、随机化、多次给药、双向交叉研究。所有患者均接受硼替佐米1.0 mg/m2 IV（在两个21天周期的第1、4、8和11天），并随机在第1或2周期的第6、7、8和9天接受酮康唑400 mg合并治疗。在周期1和周期2的第8天关闭间隔（硼替佐米给药前即刻和给药后5分钟至72小时）内采集系列血样，用于测量血浆硼替佐米浓度进行非房室PK分析，并测量血液20 S蛋白酶体抑制作用进行PD分析。所有不良事件（AE）记录在每个周期，包括严重的AE和所有的神经毒性事件，最后一剂硼替佐米后30天内，结果：21例患者（中位年龄，57岁;性别，67%男性;种族，86%白色;中位数体表面积，2.01平方米）被随机治疗。12例患者在第1周期和第2周期完成了方案规定的给药和PK采样。酮康唑对硼替佐米PK和PD影响的评估基于这12例PK可评价患者的数据。硼替佐米+酮康唑与硼替佐米单药治疗的几何平均硼替佐米AUC（0-tlast）（从时间0至末次可定量浓度的AUC）比值为1.352（90% CI，1.032-1.772）。与观察到的硼替佐米暴露的平均增加一致，伴随给予酮康唑与血液蛋白酶体抑制作用的相应增加（24%-46%）相关。结论：伴随给予CYP 3A抑制剂酮康唑与硼替佐米导致硼替佐米暴露的平均增加35%。ClinicalTrials.gov标识符：NCT 00129207。(Clin Ther. 2009;31 [主题问题]：2444-2458）（C）2009 Excerpta Medica Inc.
Background: The proteasome inhibitor bortezomib undergoes oxidative biotransformation via multiple cytochrome P450 (CYP) enzymes, with CYP3A4 identified as a partial, yet potentially important, contributor based on in vitro drug metabolism studies.Objective: The aim Of this Study was to assess the effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib.Methods: This was a prospective, Multicenter, open-label, randomized, multiple-dose, 2-way crossover study in patients with advanced solid tumors. All patients received bortezomib 1.0 mg/m(2) IV (on days 1, 4, 8, and I I of two 21-day cycles) and were randomized to receive concomitant ketoconazole 400 mg on days 6, 7, 8, and 9 of cycle 1 or 2. Serial blood samples were collected over the day-8 closing interval (Immediately prior to bortezomib administration, and from 5 minutes to 72 hours after administration) in cycles 1 and 2 for measurement of plasma bortezomib concentrations for noncompartmental PK analysis and blood 20S proteasome inhibition for PD analysis. All adverse events (AEs) were recorded during each cycle including serious AEs and all neurotoxicity events for up to 30 days after the last dose of bortezomib.Results: Twenty-one patients (median age, 57 years; sex, 67% male; race, 86% white; median body surface area, 2.01 m(2)) were randomized to treatment. Twelve patients completed the protocol-specified dosing and PK sampling in both cycles 1 and 2. Assessment of the effect of ketoconazole on bortezomib PK and PD was based on data in these 12 PK-evaluable patients. The ratio of geometric mean bortezomib AUC(0-tlast) (AUC from time 0 to last quantifiable concentration) for bortezomib plus ketoconazole versus bortezomib alone was 1.352 (90% CI, 1.032-1.772). Consistent with this observed mean increase in bortezomib exposure, concomitant administration of ketoconazole was associated with a corresponding increase (24%-46%) in the blood proteasome inhibitory effect.Conclusion: Concomitant administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a mean increase of 35%, in bortezomib exposure. ClinicalTrials.gov identifier: NCT00129207. (Clin Ther. 2009;31 [Theme Issue]:2444-2458) (C) 2009 Excerpta Medica Inc.