注射用紫杉醇（白蛋白结合型）在转移性乳腺癌患者中的暴露水平与中性粒细胞计数减少的相关性分析

Pharmacokinetics and Exposure-Toxicity Analysis of Total and Unbound Paclitaxel of Nab-paclitaxel in Patients with Metastatic Breast Cancer

关键词:  紫杉醇（白蛋白结合型）  游离紫杉醇  药动学  中性粒细胞计数

Key words:  nab-paclitaxel  unbound paclitaxel  pharmacokinetics  neutrophils

摘要:

目的 研究注射用紫杉醇（白蛋白结合型）在转移性乳腺癌患者体内总紫杉醇和游离紫杉醇的药动学（PK）参数及其与中性粒细胞计数减少的相关性。方法 纳入60例转移性乳腺癌患者接受注射用紫杉醇（白蛋白结合型）后总紫杉醇和游离紫杉醇的系列浓度，采用R软件的“PKNCA”包计算PK参数，以线性回归模型分别分析血浆总紫杉醇和游离紫杉醇暴露量与患者中性粒细胞计数减少的相关性，“pROC”包绘制受试者工作特征（ROC）曲线，探索严重中性粒细胞计数降低风险的药物阈值暴露量。结果 血浆总紫杉醇和游离紫杉醇的Cmax分别为13100±2710 ng·mL-1和677±310 ng·mL-1，AUC0-∞分别为13600± 3430 ng·h·mL-1和526±278 ng·h·mL-1，游离分数为6.00%±3.30%。血浆总紫杉醇和游离紫杉醇的AUC0-∞与中性粒细胞计数减少百分比均有显著相关性（总紫杉醇：r=0.37，p<0.01；游离紫杉醇：r=0.38，p<0.01），血浆总紫杉醇和游离紫杉醇AUC0-∞分别超过14697.50 ng·h·mL-1、646.16 ng·h·mL-1时，严重中性粒细胞计数降低的风险升高。结论 注射用紫杉醇（白蛋白结合型）的血浆总紫杉醇和游离紫杉醇的暴露（AUC0-∞）均与转移性乳腺癌患者中性粒细胞计数减少显著相关。

Abstract:

OBJECTIVE To evaluate the pharmacokinetics (PK) parameters of total and unbound paclitaxel after administration of albumin-bound paclitaxel (nab-paclitaxel), and the relationship between exposure of total or unbound paclitaxel and neutropenia in patients with metastatic breast cancer. METHODS A total of 60 patients were included in this study. The "PKNCA" package was used to calculate PK parameters of total and unbound paclitaxel in R software The correlation between paclitaxel exposure and decrease in neutrophil counts was analyzed by linear regression models. The "pROC" package was used to draw receiver operating characteristic (ROC) curve in order to screen the threshold of the risk of severe neutropenia. RESULTS The Cmax of total and unbound paclitaxel were 13100±2710 ng·mL-1 and 677±310 ng·mL-1, the AUC0-∞ were 13600± 3430 ng·h·mL-1 and 526±278 ng·h·mL-1, respectively, with free fraction of 6.00±3.30%. The reduction in neutrophil counts was significantly correlated with AUC0-∞ of total and unbound paclitaxel (total paclitaxel: r=0.37, p<0.01; unbound paclitaxel: r=0.38, p<0.01). The AUC0-∞ of total paclitaxel exceeding 14697.50 ng·h·mL-1 or 646.16 ng·h·mL-1 for unbound paclitaxel increasing the risk of grade ≥Ⅲ neutropenia. CONCLUSION Both total and unbound paclitaxel exposure were significantly correlated with decrease in neutrophil counts.