The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone:: A first in class epothilone B analogue in late-phase clinical development
The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone:: A first in class epothilone B analogue in late-phase clinical development
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DOI：
10.1158/1078-0432.ccr-07-4151
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发表时间：
2008-05-01
影响因子：
11.5
通讯作者：
Mani, Sridhar
中科院分区：
文献类型：
--
作者：
Goel, Sanjay;Cohen, Marvin;Mani, Sridhar
目的：为了确定伊沙匹隆是否是细胞色素P450 3A 4（CYP 3A 4）的底物，以及这种细胞色素对伊沙匹隆的代谢是否具有临床重要性，我们使用酮康唑作为CYP 3A 4抑制剂进行了一项人体临床药物相互作用研究。实验设计：使用人微粒体测定参与伊沙匹隆代谢的细胞色素P450酶。对埃博霉素B和伊沙匹隆进行了计算对接（CYP 3A 4）研究。在癌症患者中进行了一项后续临床研究，以确定400 mg/d酮康唑（CYP 3A 4抑制剂）是否改变了伊沙匹隆的药代动力学，药物-靶点相互作用和药效学。结果：分子建模和人类微粒体研究预测伊沙匹隆是CYP 3A 4的良好底物。在患者中，与单药治疗40 mg/m2相比，酮康唑联合给药导致伊沙匹隆的最大给药剂量为25 mg/m2。酮康唑与伊沙匹隆联合给药导致AUC（o-无穷大）增加79%，外周血单个核细胞中微管束形成与血浆伊沙匹隆浓度的关系可用Hill方程很好地描述。微管束形成在外周血单核细胞与neutralization.Conclusions：伊沙匹隆是一个很好的CYP 3A 4底物在体外，但是，在人类，它可能会被清除多种机制。此外，我们的研究结果提供了证据，伊沙匹隆的药代动力学，中性粒细胞计数和PBMC中微管束形成之间存在直接关系。在伊沙匹隆给药的情况下，应谨慎使用CYP 3A 4的强效抑制剂。
Purpose: To determine if ixabepilone is a substrate for cytochrome P450 3A4 (CYP3A4) and if its metabolism by this cytochrome is clinically important, we did a clinical drug interaction study in humans using ketoconazole as an inhibitor of CYP3A4.Experimental Design: Human microsomes were used to determine the cytochrome P450 enzyme(s) involved in the metabolism of ixabepilone. Computational docking (CYP3A4) studies were done for epothilone B and ixabepilone. A follow-up clinical study was done in patients with cancer to determine if 400 mg/d ketoconazole (inhibitor of CYP3A4) altered the pharmacokinetics, drug-target interactions, and pharmacodynamics of ixabepilone.Results: Molecular modeling and human microsomal studies predicted ixabepilone to be a good substrate for CYP3A4. In patients, ketoconazole coadministration resulted in a maximum ixabepilone dose administration to 25 mg/m(2) when compared with single-agent therapy of 40 mg/m(2). Coadministration of ketoconazole with ixabepilone resulted in a 79% increase in AUC(o-infinity), The relationship of microtubule bundle formation in peripheral blood mononuclear cells to plasma ixabepilone concentration was well described by the Hill equation. Microtubule bundle formation in peripheral blood mononuclear cells correlated with neutropenia.Conclusions: Ixabepilone is a good CYP3A4 substrate in vitro; however, in humans, it is likely to be cleared by multiple mechanisms. Furthermore, our results provide evidence that there is a direct relationship between ixabepilone pharmacokinetics, neutrophil counts, and microtubule bundle formation in PBMCs. Strong inhibitors of CYP3A4 should be used cautiously in the context of ixabepilone dosing.