药动学参数预测多西他赛血液毒性在中国早期乳腺癌患者中的应用

doi:10.5246/jcps.2016.07.056

摘要/Abstract

摘要：

应用多西他赛治疗的患者中,中性粒细胞减少是主要剂量限制性毒性。本文的目的是研究在中国早期乳腺癌患者中,多西他赛药动学指标代表的药物暴露与3–4级血液毒性(中性粒细胞减少和白细胞减少)之间的关系。患者每3周注射1次多西他赛(75 mg/m², 注射时间不少于1 h)。在第一疗程中,通过测得两个时间点(注射结束时和结束后30–60分钟)患者的多西他赛血药浓度,从而计算出由药时曲线下面积(AUC)代表的药物暴露。本次共有61名患者参与该药动学研究及毒性评估,34名(55.7%)患者出现3–4级中性粒细胞减少, 30名(49.2%)患者出现3–4级白细胞减少。多西他赛浓度具有较大个体间差异(AUC分布区间1.0–6.2 mg·h/L, 变异系数为39.6%)。导致不同程度中性粒细胞减少及白细胞减少的多西他赛平均AUC值之间具有显著差异。出现低级别(0–2级)及高级别(3–4级)中性粒细胞减少的AUC平均值分别为2.0和2.8 mg·h/L (P = 0.001), 导致白细胞减少的相应AUC平均值分别为1.9和2.9 mg·h/L (P<0.0001)。个体间多西他赛药物暴露具有异变性,通过AUC可预测高级别血液毒性的发生。确定既提高疗效又限制毒性的中国乳腺癌患者的最佳多西他赛AUC值还需要更进一步的研究。

关键词: 多西他赛, 药时曲线下面积, 毒性, 乳腺癌, 药动学/药效学

Abstract:

Neutropenia is the major dose-limiting toxicity in patients being treated with docetaxel. The purpose of this study was to evaluate the relationship between pharmacokinetically determined docetaxel exposures and grade 3–4 hematologic toxicity (neutropenia and leukopenia) in Chinese breast cancer patients.Patients received docetaxel infusions (75 mg/m² over 1 h) once every 3 weeks. At the first cycle, a patient’s docetaxel exposure was determined as an area under the curve (AUC) using plasma concentrations of docetaxel measured at two different time points (at the end of the infusion and 30–60 min later). Pharmacokinetic studies and toxicity assessments were performed for 61 patients. Grade 3–4 neutropenia occurred in 34 (55.7%) patients, and grade 3–4 leukopenia occurred in 30 (49.2%) patients. Individual exposure to docetaxel was highly variable (AUC range = 1.0–6.2 mg·h/L, inter-individual CV = 39.6%). There was a significant difference in the mean docetaxel AUC by grade of toxicity for both neutropenia and leukopenia. The average AUC for low (0–2) and high grade (3–4) neutropenia was 2.0 and 2.8 mg·h/L, respectively (P = 0.001), and for leukopenia was 1.9 and 2.9 mg·h/L, respectively (P<0.0001). 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 breast cancer patients merits further investigation.

Key words: Docetaxel, AUC, Toxicity, Breast cancer, Pharmacokinetics/pharmacodynamics

中图分类号:

R969.1

Supporting:

王芳, 陈卓, 李林, 朱明智, 熊有毅, 谷元廷. 药动学参数预测多西他赛血液毒性在中国早期乳腺癌患者中的应用[J]. 中国药学(英文版), 2016, 25(7): 512-516.

Fang Wang, Zhuo Chen, Lin Li, Mingzhi Zhu, Youyi Xiong, Yuanting Gu. Pharmacokinetically determined docetaxel exposure as a predictor of hematologic toxicity in Chinese patients with early stage breast cancer[J]. Journal of Chinese Pharmaceutical Sciences, 2016, 25(7): 512-516.

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