多西他赛药动学参数在减少晚期卵巢癌患者血液毒性预测中的应用

The role of pharmacokinetic monitoring of docetaxel in reduction of hematologic toxicity for patients with advanced cervical cancer

目的:回顾性分析79例晚期卵巢癌患者化疗后多西他赛(docetaxel,DOC)药动学指标代表的药物暴露与血液毒性之间的关系,明确其在进一步减少血液毒性中的作用。方法:79例晚期卵巢癌患者接受多西他赛+奈达铂方案(DOC 75mg·m-2静滴,第2天静滴奈达铂80mg·m-2,21d为一周期)化疗,于化疗第1周期监测患者DOC血药浓度,包括滴注结束前(5±5)min和滴注结束后(45±15)min两个血液样本浓度,从而计算出由药时曲线下面积(area under the curve,AUC)代表的药物暴露;化疗1周后评价不良反应,分析多西他赛药时曲线下面积(DOC-AUC)与血液毒性不良反应的相关性。结果:79例中国晚期卵巢癌患者DOC-AUC值范围为1.2~3.8 mg·h·L^(-1),平均AUC(±SD)为(2.60±0.56)mg·h·L^(-1),变异系数(CV)为24.55%,其AUC符合正态分布。27例(34.2%)患者出现Ⅲ~Ⅳ级中性粒细胞减少,29例(36.7%)患者出现Ⅲ~Ⅳ级白细胞减少,17例(21.5%)患者出现Ⅲ~Ⅳ级血红蛋白减少。未发生血液毒性不良反应组(0级)和发生组(Ⅰ~Ⅳ级)DOC-AUC值有显著性差异(P<0.05);出现低级别(0~Ⅱ级)及高级别(Ⅲ~Ⅳ级)中性粒细胞减少症的AUC平均值分别为(2.12±0.49)和(2.62±0.55)mg·h·L^(-1)(P=0.000 1),导致白细胞减少的相应AUC平均值分别为(2.14±0.68)和(2.67±0.49)mg·h·L^(-1)(P=0.008),发生不同程度中性粒细胞减少症和白细胞减少不良反应的DOC-AUC值之间差异有显著性(P<0.05)。结论:相同体表面积剂量给药,DOC-AUC值存在个体间差异,DOC-AUC值的不同影响了药物血液毒性不良反应的严重程度,DOC-AUC值可预测血液毒性的发生。确定既提高疗效又限制毒性的中国卵巢癌患者的最佳多西他赛AUC值还需要更进一步的研究。

OBJECTIVE To evaluate the relationship between pharmacokinetically determined docetaxel exposures and gradeⅢ～Ⅳ hematologic toxicity（neutropenia and leukopenia）in Chinese advanced cervical cancer patients.METHODS Patients received docetaxel infusions（75 mg·m^-2 over 1 honce every 3 weeks）.Blood samples were collected before（5±5）min and after（45±15）min at the end of the infusion in the first cycle to monitor the concentrations of docetaxel and determine the docetaxel exposure from the area under the curve（AUC）.The adverse reactions of chemotherapy were analyzed and evaluated statistically after one week to analyze the relationship between pharmacokinetic parameter AUC and hematologic toxicity of docetaxel.RESULTS Pharmacokinetic studies and toxicity assessments were performed for 79 patients.GradeⅢ-Ⅳ neutropenia occurred in 27（34.2%）patients,and grade Ⅲ-Ⅳ leukopenia occurred in 29（36.7%）patients.Individual exposure to docetaxel was highly variable（AUC range=1.2-3.8 mg·h·L^-1,inter-individual CV=24.55%）.There was a significant difference in the mean docetaxel AUC by grade of toxicity for both neutropenia and leukopenia.The average AUCs for low（0-Ⅱ）and high grade（Ⅲ-Ⅳ）neutropenia was（2.12±0.49）and（2.62±0.55）mg·h·L^-1,respectively（P=0.000 1）,and for leukopenia were（2.14±0.6）and（2.67±0.49）mg·h·L^-1,respectively（P=0.008）.CONCLUSION Individual exposure to docetaxel is variable and predictive of high grade hematologic toxicity.The optimal docetaxel AUC to maximize efficacy and minimize toxicity in Chinese advanced cervical cancer patients merits further investigation.