多西他塞合用顺铂的Ⅰ期临床药动学研究

A phase Ⅰ clinical pharmacokinetic study for docetaxel in combination with cisplatin

目的:研究多西他塞(泰索帝)在与顺铂联合用药情况下的药动学特征,确定和推荐Ⅱ期临床试验的给药方案。方法:选择晚期转移ⅢB或Ⅳ期非小细胞肺癌(NSCLC)患者15例,分成4组,分别按25,30,35,40mg·m-2剂量,每周1次方案给药,在每28d中的d1,8,15静注给药,4个剂量组均按75mg·m-2固定剂量给予顺铂。在第1周期的d1和d15给药前即刻,静注30min给药结束即刻,给药结束后10,30,45,60,90min及3,5,8,12,24h分别采血,用LC/MS/MS测定血药浓度。用WinNonlin软件按恒速静脉输注给药的三室模型进行分析并计算相关药动学参数。经对数转换的药动学参数包括剂量归一化的AUCN,Cmax和Cl,用SAS Proc混合程序进行检验。结果:在给药d1,当剂量从25增加到40mg·m-2时,平均AUC值从(1 393±288)增加到(1 968±757)μg·h·L-1;d15平均AUC值从(1 423±149)增加到(1 751±564)μg·h·L-1。在给药d1和d15,CmaxN,AUCN及Cl值均无显著性差异。结论:多西他塞静脉给药后Cmax和AUC值与剂量成比例增加,而Cl值与剂量水平无关,其药动学不受合用顺铂的影响。

Objective:To characterize the pharmacokinetics of docetaxel in combination with cisplatin. Methods: 15 patients with advanced or metastatic (stage Ⅲ B or Ⅳ) NSCLC were divided in-to four groups.Each group received a dose of docetaxel i. v. infusion at 25,30,35,40mg·m-2 in 30 minutes once per week,respectively. A dose of cisplatin at 75mg·m-2 was added into the i. v. infusion of docetaxel at day 1 in a period of 28 days treatment. At the day 1 and day 15 blood samples were col-lected immediately before and after the infusion,and also at 10,30,45,60,90min,3,5,8,12,24h after every infusion. Concentration of docetaxel in combination with cisplatin was determined by LC/MS/ MS. Pharmacokinetic profile was analyzed by a three-compartment kinetic model with constant i. v. in-put (WinNonlin V2.1). Log-transformed pharmacokinetic parameters including dose normalised AUCN, CmaxN and Cl were calculated by the SAS Proc mixed. Results: When the infusion dose of docetaxel was escalated from 25mg·m-2 to 40mg·m-2,the mean AUC increased from (1393±288) to (1 968±757)μg·h·L-1 at day 1,and from (1 423±149) to (1 751±564)μg·h·L-1 at day 15.No statistically significant difference between day 1 and day 15 was observed in AUCN, CmaxN and Cl. Conclusion: Cmax and AUC value was proportionally increased with the increasing dose. The Cl value has no coorelationship with the dose administrated. The pharmacokinetic profile of docetaxel was not affected by the cisplatin co-administration.