Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel
Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel
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DOI：
10.1016/j.clpt.2004.01.001
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发表时间：
2004-05-01
影响因子：
6.7
通讯作者：
Sparreboom, A
中科院分区：
文献类型：
--
作者：
Engels, FK;ten Tije, AJ;Sparreboom, A
目的：体外研究表明，抗癌药物多西他赛主要通过细胞色素P450 (CYP) 3a4介导的代谢消除。因此，同时使用调节CYP3A4活性的药物可能会产生不良的临床后果。我们研究了强效CYP3A4抑制剂酮康唑对癌症患者多西紫杉醇药代动力学的影响。方法：7例患者采用随机交叉设计，多西他赛（100 mg/m(2)）治疗，3周后多西他赛（10 mg/m2）联合口服酮康唑（200 mg，每日1次，连用3天），或相反顺序。血浆浓度-时间数据采用非室间分析。结果：酮康唑联合用药使多西他赛清除率降低49% （P= 0.018）。多西他赛单独组的平均（+/- sd）清除率为35.0 +/- 11.8 L/h(95%可信区间为24.1-45.9 L/h)，酮康唑组的平均（+/- sd）清除率为18.2 L/h（95%可信区间为9.22-27.1 L/h）。酮康唑存在和不存在时，多西他赛清除率与酮康唑曲线下面积呈弱相关（R-2 = 0.529, P = 0.064）。结论：酮康唑在体内抑制CYP3A4导致多西他赛清除率，先前已被证明与标准剂量下发热性中性粒细胞减少的几率增加数倍相关。如果多西他赛必须与强效CYP3A4抑制剂一起使用，则应谨慎使用，并需要大幅减少剂量。
Objective: In vitro studies indicate that the anticancer drug docetaxel is primarily eliminated by cytochrome P450 (CYP) 3A4-mediated metabolism. Coadministration of drugs that modulate the activity of CYP3A4 is, therefore, likely to have undesirable clinical consequences. We investigated the effects of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of docetaxel in patients with cancer.Methods: Seven patients were treated in a randomized crossover design with docetaxel (100 mg/m(2)), followed 3 weeks later by docetaxel (10 mg/m2) given in combination with orally administered ketoconazole (200 mg once daily for 3 days), or the reverse sequence. Plasma concentration-time data were analyzed by noncom-partmental analysis.Results: Ketoconazole coadministration resulted in a 49% decrease in clearance of docetaxel (P=.018). The mean ( +/-SD) clearance values were 35.0 +/- 11.8 L/h (95% confidence interval, 24.1-45.9 L/h) for docetaxel alone and 18.2 L/h (95% confidence interval, 9.22-27.1 L/h) in the presence of ketoconazole, respectively. The docetaxel clearance ratio in the presence and absence of ketoconazole was weakly related to the area under the curve of ketoconazole (R-2 = 0.529, P =.064).Conclusion: Inhibition of CYP3A4 by ketoconazole in vivo results in docetaxel clearance values that have previously been shown to be associated with a several-fold increase in the odds for febrile neutropenia at standard doses. Caution should be taken and substantial dose reductions are required if docetaxel has to be administered together with potent inhibitors of CYP3A4.