Phase I combining a P-glycoprotein inhibitor, MS209, in combination with docetaxel in patients with advanced malignancies
Phase I combining a P-glycoprotein inhibitor, MS209, in combination with docetaxel in patients with advanced malignancies
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DOI：
10.1158/1078-0432.ccr-04-2316
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发表时间：
2005-09-01
影响因子：
11.5
通讯作者：
Fumoleau, P
中科院分区：
文献类型：
--
作者：
Diéras, W;Bonnieterre, J;Fumoleau, P
目的：本研究的目的是调查的安全性和耐受性的MS 209，一种有效的P-糖蛋白抑制剂，当与多西他赛联合使用，并确定是否MS 209影响多西他赛的药代动力学。实验设计：晚期实体恶性肿瘤患者有资格参加这一I期试验。在第一个周期中，单独给予多西他赛1小时输注。从第2周期开始引入MS 209，并在多西他赛输注后30分钟口服给药。剂量递增方案遵循改良的Fibonacci模型，分为6个步骤（多西他赛60-100 mg/m2，MS 209 300- 1200 mg/人）。剂量限制性毒性为发热性中性粒细胞减少症、感染、口腔炎、吞咽困难和疲乏。最大耐受剂量达到水平5（多西他赛，80-MS：1，200）。药代动力学分析未显示两种药物之间存在较强的药代动力学相互作用，但在最高剂量水平下，多西他赛与MS 209联合给药时，其AUC有增加的趋势。结论：MS 209可与多西他赛联合给药，对多西他赛的毒性和药代动力学影响有限。
Purpose: The purpose of this study was to investigate the safety and tolerability of MS209, a potent inhibitor of P-glycoprotein, when given in combination with docetaxel and to determine whether MS209 affects docetaxel pharmacokinetics.Experimental design: Patients with advanced solid malignancies were eligible for this phase I trial. Docetaxel as 1-hour infusion was given alone during the first cycle. MS209 was introduced as of cycle 2 and given orally 30 minutes after docetaxel infusion. The dose escalation scheme followed a modified Fibonacci model with six steps (docetaxel, 60-100 mg/m(2) and MS209, 300-1,200 mg per body).Results: A total of 30 patients were treated at five dose levels. Dose-limiting toxicities were febrile neutropenia, infection, stomatitis, dysphagia, and fatigue. The maximum tolerated dose was reached at level 5 (docetaxel, 80-MS: 1,200). Pharmacokinetic analysis failed to show a strong pharmacokinetic interaction between the two compounds, but at the highest dose levels, there is a trend to an increase of docetaxel AUC when this agent is given in combination with MS209.Conclusion: MS209 can be given in combination with docetaxel, with limited effect on docetaxel toxicity or pharmacokinetics.