Docetaxel and ketoconazole in advanced hormone-refractory prostate carcinoma - A phase I and pharmacokinetic study
Docetaxel and ketoconazole in advanced hormone-refractory prostate carcinoma - A phase I and pharmacokinetic study
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DOI：
10.1002/cncr.11733
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发表时间：
2003-11-01
期刊：
影响因子：
6.2
通讯作者：
Williamson, S
中科院分区：
文献类型：
--
作者：
Van Veldhuizen, PJ;Reed, G;Williamson, S
背景资料。多西紫杉醇在前列腺癌患者中具有显著的单药活性，酮康唑具有作为二线激素剂的活性。在体外，酮康唑与几种化疗药物显示出协同作用。然而，存在潜在的药物相互作用，因为多西紫杉醇和酮康唑都是通过细胞色素P450系统(CYP3A4)在肝脏代谢的。作者进行了一项I期研究和药代动力学研究，评估了多西紫杉醇/酮康唑联合用药的耐受性以及这种潜在的药物相互作用。方法：对于所有的初始患者，多西紫杉醇以55 mg/m(2)的剂量静脉注射，每21天持续1小时。从第一次多西他赛剂量后第8天开始，至少有3-5名新患者入选队列，接受递增剂量的酮康唑治疗。当达到酮康唑的最大耐受量(MTD)时，随后的患者队列接受递增剂量的多西紫杉醇。多西紫杉醇在第1天(在酮康唑之前)和第22天(在开始使用酮康唑之后)进行了药代动力学研究。结果：26名患者入选并完成了至少2个周期的治疗。MTD用药酮康唑400 mg，每日2次，多西紫杉醇55 mg/m~2。剂量限制毒性包括中性粒细胞减少和疲劳。酮康唑对多西紫杉醇的药代动力学影响并不一致，尽管患者内和患者间的血药浓度存在显著差异。结论：该联合用药的推荐二期剂量为酮康唑400 mg，每日两次，多西紫杉醇55 mg/m(2)，每21天一次。2003年由美国癌症协会出版。
BACKGROUND. Docetaxel has significant single-agent activity in patients with prostate carcinoma, and ketoconazole has activity as a second-line hormonal agent. In vitro, ketoconazole exhibits synergy with several chemotherapeutic agents. A potential drug interaction exists, however, because both docetaxel and ketoconazole are metabolized hepatically by the cytochrome p450 system (CYP3A4). The authors performed a Phase I study and a pharmacokinetic study evaluating the both tolerability of a docetaxel/ketoconazole combination as well as this potential drug interaction.METHODS. For all initial patients, docetaxel was administered intravenously at a dose of 55 mg/m(2) over 1 hour every 21 days. Starting on Day 8 after their first docetaxel dose, cohorts of at least 3-5 new patients were enrolled to receive escalating doses of ketoconazole. When the maximally tolerated dose (MTD) of ketoconazole was reached, the subsequent cohort of patients received an escalating dose of docetaxel. Pharmacokinetic studies were performed after docetaxel infusions on Day 1 (prior to ketoconazole) and Day 22 (after starting ketoconazole).RESULTS. Twenty-six patients were enrolled and completed at least 2 cycles of treatment. The MTD was ketoconazole 400 mg twice daily and docetaxel 55 mg/m(2). Dose-limiting toxicities included neutropenia and fatigue. Ketoconazole did not cause a consistent effect on docetaxel pharmacokinetics, although there was significant intrapatient and interpatient variability in serum levels.CONCLUSIONS. The recommended Phase II dose for this combination is ketoconazole 400 mg twice daily and docetaxel 55 mg/m(2) every 21 days. Published 2003 by the American Cancer Society.