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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。
Among patients treated with docetaxel, neutropenia is the major dose-limiting toxicity. The purpose of this study was to investigate the relationship between drug exposure, which is indicated by the docetaxel pharmacokinetics, and grade 3-4 hematotoxicity (neutropenia and leukopenia) in Chinese patients with early-stage breast cancer. Patients received docetaxel once every 3 weeks (75 mg / m2, injection time of not less than 1 h). During the first course of treatment, the drug, represented by the area under the pharmacokinetic profile (AUC), was calculated by measuring the plasma concentration of docetaxel at two time points (at the end of the injection and 30-60 minutes after the end) Exposed. A total of 61 patients participated in the pharmacokinetic study and toxicity assessment. Grade 3-4 neutropenia occurred in 34 (55.7%) patients and grade 3-4 leucopenia occurred in 30 (49.2%) patients. Docetaxel concentration had larger inter-individual differences (AUC distribution range 1.0-6.2 mg · h / L, coefficient of variation of 39.6%). There was a significant difference between mean AUC values of docetaxel resulting in varying degrees of neutropenia and leukopenia. The mean AUCs for both low (grade 0-2) and high (grade 3-4) neutropenia were 2.0 and 2.8 mg · h -1 (P = 0.001), respectively, with corresponding AUCs leading to leukopenia Values were 1.9 and 2.9 mg · h / L, respectively (P <0.0001). Individualized docetaxel drug exposure is a variant that predicts high-grade hematologic toxicity by AUC. The determination of the best docetaxel AUC in Chinese patients with breast cancer, which not only improves curative effect but also limits toxicity, needs further study.