多西他赛血药浓度监测在肿瘤患者DP方案化疗中的应用

【作者】 郭林； 彭昊； 唐丹； 胡皓； 蔡骅琳； 王峰； 马进安； 颜苗；

【Author】 Yan Miao;

【机构】 中南大学湘雅二医院药学部； 中南大学湘雅二医院肿瘤科；

【摘要】 目的:为满足临床常规监测的需求,建立肿瘤患者血浆中多西他赛浓度测定的一种高效灵敏的LC-MS/MS方法,并探讨在DP化疗方案中NK-1止吐剂阿瑞匹坦（CYP3A4抑制剂）不同给药方式对多西他赛（CYP3A4底物）药动学的影响差异。方法:24位肿瘤患者给予高致吐DP化疗方案（多西他赛75mg/m² d1+顺铂25mg/m² d1-3）,进行前瞻性的随机自身前后对照试验,洗脱期为3周。第一周期（A方案）口服阿瑞匹坦125mgd1,80mgd2-3（多西他赛化疗前1小时给予）,第二周期（B方案）延迟一天给药,即口服阿瑞匹坦125mgd2,80mgd3-4,其他辅助药物基本一致。化疗第一天于多西他赛静滴前、静滴0.5h时、静滴完成后0, 0.17, 0.5, 1, 2.5, 5, 10, 24h对患者进行静脉采血,基于LC-MS/MS高分离能力和高灵敏度等优势,样品液液萃取处理后经含0.1%甲酸的乙腈/含0.1%甲酸的水=85:15（v/v）流动相在Xtimate^TMC₁₈（2.1×150mm,3.0μm）柱上进行色谱分离,然后通过多反应监测串联质谱测定血药浓度,再对两方案主要药动学参数进行非房室模型分析。结果:所建立的测定方法分析时间为3.2min,线性范围为5.0-1500ng/ml,提取回收率为83.4-102.5%,精密度、准确度RSD均≤15%。通过数据分析提示阿瑞匹坦与多西他赛同时给药并不影响多西他赛药动学。A/B两方案主要参数比较如下:AUC_0-t（μg*h/ml）为1.134±0.733vs1.081±0.585（P> 0.05,A/B=104.9）, C_max（μg/ml）为1.026±0.580 vs 1.003±0.526（P>0.05,A/B=102.3）,CL（l/h/m²）为89.284±57.503 vs 92.845±89.148（P>0.05,A/B=96.2）。讨论:本研究建立的测定方法专属性强,报告周期时间短,适用于临床上开展多西他赛血药浓度监测和在中国肿瘤患者人群中的药动学研究。常规DP化疗方案中阿瑞匹坦不影响多西他赛的药动学,但结果显示多西他赛清除率较国外报道高达4倍以上,个体间差异明显,且多西他赛血药浓度普遍偏低,亟需进行治疗药物监测,进行个体化给药。CYP3A5*3C基因多态性存在显著的种族差异,提示可能是个体化差异明显的一个重要因素,有待进一步研究。更多还原

【Abstract】 Objective: In order to meet the needs of routine clinical monitoring,an efficient and sensitive LC-MS/MS method for determination of docetaxel in plasma of patients with tumors was established, and then explored the effect of different administration methods of NK-1 antiemetic aprepitant（CYP3A4 inhibitor） on the pharmacokinetics of docetaxel（CYP3A4 substrate） in DP chemotherapy regimen.Methods:Twenty-four patients with tumors were treated with a high vomiting regimen（docetaxel 75 mg/m² d1 + cisplatin 25 mg/m² d1-3） for a prospective and randomized self-controlled trial,and a washout period was 3 weeks.In the first cycle（regimen A）, oral aprepitant 125 mg d1, 80 mg d2-3（administered 1 hour before docetaxel chemotherapy）, and the second cycle（regimen B） was delayed for one day,scilicet oral aprepitant 125 mg d2, 80 mg d3-4, and other auxiliary drugs are basically the same. On the first day of chemotherapy, venous blood was collected before intravenous infusion of docetaxel, 0.5 h after intravenous infusion, and 0, 0.17, 0.5, 1, 2.5, 5, 10, 24 h after completion of intravenous infusion.Based on the advantages of LC-MS/MSsuch as strong isolation ability and high sensitivity,the sample was extracted by liquid-liquid extraction and thenchromatographed on a XtimateTMC₁₈（2.1×150 mm, 3.0 μm） column with the mobile phase of 0.1% formic acid in acetonitrile/0.1% formic acid in water=85:15（v/v）,followed by multi-reaction monitoring tandem mass spectrometry to monitor drug concentration. the non-compartmental model analysis was performed for the main pharmacokinetic parameters of the two schemes.Results:The determination method has an analysis time of 3.2 min, the linear range was 5.0-1500 ng/ml, the extraction recovery was 83.4-102.5%, and the precision and accuracy RSD was of ≤15%. Data analysis indicated that the simultaneous administration of aprepitant and docetaxel did not affect docetaxel pharmacokinetics. The main parameters of the A/B scheme are as follows:AUC_0-t（μg*h/ml）:1.134±0.733 vs1.081±0.585（P>0.05,A/B=104.9）,C_max（μg/ml）:1.026± 0.580 vs 1.003± 0.526（P>0.05,A/B=102.3）, CL（l/h/m²）:89.284± 57.503 vs 92.845 ± 89.148（P > 0.05,A/B=96.2）.Discussion:The established determination method has a high specificity and short reporting period, which is suitable for therapeutic drug monitoring of docetaxel and pharmacokinetic studies in Chinese tumor patients. In the routine DP chemotherapy regimen, aprepitant did not affect the pharmacokinetics of docetaxel, but the results showed that the clearance of docetaxel was more than 4 times higher than that reported in foreign countries. The difference between individuals was obvious, moreover the concentration of docetaxel was generally low, so therapeutic drug monitoringis an urgent need to provide individual administering services. There is a significant racial difference in the CYP3A5*3 C gene polymorphism, suggesting that it may be an important factor in the individualized differences, whichshould be further explored.更多还原