Effect of the Cytochrome P450 2C19 Inhibitor Omeprazole on the Pharmacokinetics and Safety Profile of Bortezomib in Patients with Advanced Solid Tumours, Non-Hodgkin's Lymphoma or Multiple Myeloma
Effect of the Cytochrome P450 2C19 Inhibitor Omeprazole on the Pharmacokinetics and Safety Profile of Bortezomib in Patients with Advanced Solid Tumours, Non-Hodgkin's Lymphoma or Multiple Myeloma
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DOI：
10.2165/00003088-200948030-00006
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发表时间：
2009-01-01
影响因子：
4.5
通讯作者：
Dudov, Assen
中科院分区：
文献类型：
--
作者：
Quinn, David I.;Nemunaitis, John;Dudov, Assen
背景和目的：硼替佐米是一种治疗复发性多发性骨髓瘤和套细胞淋巴瘤的药物，通过细胞色素P450（CYP）酶（主要是CYP 3A 4和CYP 2C 19）的氧化脱硼作用进行代谢。奥美拉唑是一种质子泵抑制剂，主要由CYP 2C 19代谢，并对CYP 2C 19表现出高亲和力。本研究调查了奥美拉唑联合给药是否影响硼替佐米在晚期癌症患者中的药代动力学、药效学和安全性特征。硼替佐米的药代动力学的变异性与β-内酰胺酶多态性也investigated.Patients和方法：这开放标签，交叉，药代动力学药物相互作用的研究进行了7个机构在美国和欧洲之间的2005年1月和2006年8月。患有晚期实体瘤、非霍奇金淋巴瘤或多发性骨髓瘤、年龄≥ 18岁、体重≥ 50公斤、预期寿命≥ 3个月的患者符合资格。患者在第1、4、8和11天接受硼替佐米1.3 mg/m2治疗，共21天为1个周期，在第1周期（序列1）或第2周期（序列2）第6-10天早晨和第8天晚上接受奥美拉唑40 mg治疗。在第2周期的第21天，从治疗中获益的患者可以继续接受硼替佐米治疗6个周期。在第1和2周期第8天硼替佐米给药前和给药后的不同时间点采集用于药代动力学/药效学评价的血样。还采集了用于药物基因组学的血液样本。使用WinNonlinTM 4.0.1.a版软件，通过在周期1和2的第8天硼替佐米给药的血浆浓度-时间数据的非房室分析计算药代动力学参数。使用全血20 S蛋白酶体抑制assay.Results的药效学概况进行了评估：27例患者（中位年龄64岁）入组，12序列1和15序列2，包括8和9药代动力学评价的患者，分别。当硼替佐米单独给药或与奥美拉唑联合给药时，硼替佐米药代动力学参数相似（最大血浆浓度120 vs 123 ng/mL; 0 - 72小时血浆浓度-时间曲线下面积129 vs 135 ng）。h/mL）。药效学参数也相似（最大效应85.8% vs 93.7%; 72小时内抑制-时间曲线下面积百分比4052 vs 3910% x h）;差异无统计学显著性。药物基因组学分析显示，β-内酰胺酶多态性和药代动力学/药效学参数之间没有有意义的关系。序列1和序列2中患者之间以及两个治疗序列中周期1和周期2之间的毒性通常相似。在26个可评估的患者中，13（50%）被评估为受益于硼替佐米在第2周期结束时，并继续接受treatment.Conclusions：没有影响的药代动力学，药效学和安全性的硼替佐米与奥美拉唑的共同管理。硼替佐米和奥美拉唑合并给药不太可能引起具有临床意义的药物相互作用，也不太可能对硼替佐米的疗效或安全性产生影响。
Background and objective: Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated.Patients and methods: This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma, were aged >= 18 years, weighed >= 50 kg and had a life expectancy of >= 3 months were eligible. Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6-10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood samples for pharmacokinetic/pharmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood samples for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin (TM) version 4.0.1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay.Results: Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively. Bortezomib pharmacokinetic parameters were similar when bortezomib was administered alone or with omeprazole (maximum plasma concentration 120 vs 123 ng/mL; area under the plasma concentration-time curve from 0 to 72 hours 129 vs 135 ng . h/mL). The pharmacodynamic parameters were also similar (maximum effect 85.8% vs 93.7%; area under the percent inhibition-time curve over 72 hours 4052 vs 3910 % x h); the differences were not statistically significant. Pharmacogenomic analysis revealed no meaningful relationships between CYP enzyme polymorphisms and pharmacokinetic/pharmacodynamic parameters. Toxicities were generally similar between patients in sequence 1 and sequence 2, and between cycle 1 and cycle 2 in both treatment sequences. Among 26 evaluable patients, 13 (50%) were assessed as benefiting from bortezomib at the end of cycle 2 and continued to receive treatment.Conclusions: No impact on the pharmacokinetics, pharmacodynamics and safety profile of bortezomib was seen with coadministration of omeprazole. Concomitant administration of bortezomib and omeprazole is unlikely to cause clinically significant drug-drug interactions and is unlikely to have an impact on the efficacy or safety of bortezomib.