Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects
Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects
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DOI：
10.1007/s00280-003-0722-9
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发表时间：
2004-02-01
影响因子：
3
通讯作者：
Seiberling, M
中科院分区：
文献类型：
--
作者：
Bolton, AE;Peng, B;Seiberling, M
客观的。本研究旨在探讨利福平诱导 CYP3A 对伊马替尼（格列卫）暴露的影响。方法。该研究采用单中心、单序列设计。一组 14 名健康男性和女性受试者两次接受伊马替尼单次 400 mg 口服剂量：研究第 1 天和研究第 15 天。在研究第 8 天开始用于 CYP4503A 诱导的利福平治疗（600 mg 每天一次）并维持到第 18 天。在第 1 天（无诱导）和第 15-18 天给药后 96 小时内测定伊马替尼药代动力学（同时服用利福平期间）。使用 LC/MS/MS 方法测定伊马替尼及其主要代谢物 CGP74588 的血浆浓度。测量 6β-羟基皮质醇与尿液中排泄的皮质醇的比率以监测 CYP3A 的诱导。结果。同时服用利福平期间，伊马替尼平均 C-max、AUC(0-24) 和 AUC(0-无穷大) 分别降低 54% (90% CI: 48-60%)、68% (64-70%) 和 74% (71-76%)。利福平治疗期间清除率 (Cl/f) 增加了 385% (348-426%)。利福平预处理后，代谢物CGP74588的平均C-max和AUC(0-24)分别增加88.6%(68.3%-111.4%)和23.9%(13.5%-35.2%)。然而，AUC（0-无穷大）下降了 11.7%（3.3-19.4%）。通过平均基线浓度 5.6 U 至 50.5 U 的 6β-羟基皮质醇与皮质醇的排泄比率进行分析，所有受试者均表现出肝微粒体 CYP3A 的显着诱导。结论。同时使用伊马替尼和利福平或其他 CYP4503A 强效诱导剂可能会导致伊马替尼血浆浓度低于治疗水平。对于服用利福平或其他 CYP3A 诱导剂的患者，应选择酶诱导潜力较小的替代治疗药物。
Objective. This study was carried out to investigate the influence of CYP3A induction with rifampicin on imatinib (Gleevec) exposure. Methods. The study employed a single center, single-sequence design. A group of 14 healthy male and female subjects received imatinib as a single 400 mg oral dose on two occasions: on study day 1 and on study day 15. Rifampicin treatment (600 mg once daily) for CYP4503A induction was initiated on study day 8 and maintained until day 18. Imatinib pharmacokinetics were determined up to 96 h after dosing on day 1 (no induction) and on days 15-18 (during concomitant rifampicin). Plasma concentrations of imatinib and its main metabolite CGP74588 were determined using a LC/MS/MS method. The ratio of 6beta-hydroxycortisol to cortisol excreted in the urine was measured to monitor the induction of CYP3A. Results. During concomitant rifampicin administration, the mean imatinib C-max, AUC(0-24) and AUC(0-infinity) decreased by 54% (90% CI: 48-60%), 68% (64-70%) and 74% (71-76%), respectively. The increase in clearance (Cl/f) was 385% (348-426%) during rifampicin treatment. The mean C-max and AUC(0-24) of the metabolite CGP74588 increased by 88.6% (68.3%-111.4%) and 23.9% (13.5%-35.2%) after rifampicin pretreatment. However, the AUC(0-infinity) decreased by 11.7% (3.3-19.4%). All subjects demonstrated a marked induction of hepatic microsomal CYP3A analyzed by the excretion ratio of 6beta-hydroxycortisol to cortisol from a mean baseline concentration of 5.6 U to 50.5 U. Conclusion. Concomitant use of imatinib and rifampicin or other potent inducers of CYP4503A may result in subtherapeutic plasma concentrations of imatinib. In patients in whom rifampicin or other CYP3A inducers are prescribed, alternative therapeutic agents with less potential for enzyme induction should be selected.