多西他赛在乳腺癌病人中群体药代动力学模型的验证

程金泉; 石庆平; 刘哲; 孔令提; 余美玲

doi:10.13898/j.cnki.issn.1000-2200.2020.05.022

多西他赛在乳腺癌病人中群体药代动力学模型的验证

Validation of the population pharmacokinetic model of docetaxel in breast cancer patients

摘要

摘要:
目的探讨已建立的不同多西他赛群体药代动力学（PPK）模型对国内乳腺癌群体的适用性，从而为建立合适的国内乳腺癌病人最终PPK模型提供依据。
方法计算机检索PubMed、Embase、Web of Science、中国知网和万方等数据库中多西他赛PPK模型的文献，提取文献基本信息，收集国内乳腺癌病人应用多西他赛的血药浓度数据，利用Phoenix非线性最大混合效应模型软件进行拟合，根据模型拟合的观测浓度-预测浓度诊断图与可视化预测检验评估已有模型对乳腺癌病人血药浓度的拟合效果。
结果共收集39例乳腺癌病人108个血药浓度数据作为外部验证数据集进行多西他赛PPK模型验证。最终纳入研究的文献有6篇。对建立的PPK模型进行拟合后发现LAUNAY-ILIADIS模型拟合效果最佳（-2LL=933.34，AIC=993.34），BRUNO模型次之（-2LL=945.13，AIC=1007.13），其余模型拟合效果较差。
结论国内多西他赛治疗乳腺癌的血药浓度数据与大多数文献报道的多西他赛PPK模型拟合效果不佳，为研究国内多西他赛治疗乳腺癌病人的药动学特征，有必要建立多中心、大样本的国内乳腺癌多西他赛PPK模型。

Abstract:
ObjectiveTo explore the applicability of different docetaxel population pharmacokinetic(PPK) models in domestic breast cancer population, so as to provide a basis for establishing a suitable PPK model for domestic breast cancer patients.
MethodsThe literatures of docetaxel PPK model in PubMed, Embase, Web of Science, CNKI, and WanFang databases were searched by computer, the basic information of literature was extracted, the blood concentration data of docetaxel in domestic breast cancer patients were collected and fitted using Phoenix nonlinear mixed-effects model software.The fitting effects of blood drug concentration in breast cancer patients were analyzed using the diagnostic graph of observed concentration-predicted concentration of model fitting and visual predictve checks.
ResultsA total of 108 blood drug concentration data in 39 breast cancer patients were collected as external validation data sets to verify the docetaxel PPK model.Finally, 6 literatures were included in the study.The results of the established PPK model fitting found that LAUNAY-ILIADIS model had the best fitting effects(-2LL=933.34, AIC=993.34), followed by BRUNO model(-2LL=945.13, AIC=1 007.13), and the other models had the poor fitting effects.
ConclusionThe blood concentration data of docetaxel in the treatment of breast cancer in China do not fit well with the PPK model of docetaxel reported in most literatures.In order to study the pharmacokinetic characteristics of docetaxel for domestic breast cancer patients, it is necessary to establish a multi-center and large-sample PPK model for domestic breast cancer patients.

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