Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Clin Ther. 2009;31 Pt 2:2444-58. doi: 10.1016/j.clinthera.2009.11.012.
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.
The aim of this study was to assess the effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib.
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 11 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 dosing 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.
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.
Concomitant administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a mean increase of 35% in bortezomib exposure. ClinicalTrials.gov identifier: NCT00129207.
硼替佐米是一种蛋白酶体抑制剂，可通过多种细胞色素 P450（CYP）酶发生氧化生物转化，体外药物代谢研究表明 CYP3A4 是部分但可能重要的贡献者。
本研究旨在评估酮康唑同时给药对硼替佐米药代动力学（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、多剂量、2 向交叉研究。所有患者均接受硼替佐米 1.0mg/m2 静脉注射（在两个 21 天周期的第 1、4、8 和 11 天），并随机接受酮康唑 400mg 同时给药，分别在第 1 周期和第 2 周期的第 6、7、8 和 9 天。在第 1 周期和第 2 周期中，在第 8 天给药间隔内（在硼替佐米给药前立即，以及给药后 5 分钟至 72 小时）采集连续血样，用于非房室 PK 分析测定血浆硼替佐米浓度和用于 PD 分析的血液 20S 蛋白酶体抑制作用。记录每个周期中的所有不良事件（AE），包括严重 AE 和最后一次硼替佐米给药后 30 天内的所有神经毒性事件。
21 名患者（中位年龄 57 岁；性别，67%为男性；种族，86%为白人；中位体表面积，2.01m2）被随机分配至治疗组。12 名患者完成了第 1 周期和第 2 周期中所有规定剂量和 PK 采样。根据这 12 名 PK 可评估患者的数据，评估酮康唑对硼替佐米 PK 和 PD 的影响。硼替佐米加酮康唑与硼替佐米单用时的硼替佐米 AUC（0-tlast）（从时间 0 到最后可定量浓度的 AUC）几何均数比值为 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，酮康唑同时给药与血液蛋白酶体抑制作用相应增加（24%-46%）相关。
与硼替佐米同时给予 CYP3A 抑制剂酮康唑导致硼替佐米暴露量平均增加 35%。临床试验.gov 标识符：NCT00129207。
