基于NONMEM法建立紫杉醇群体药动学模型

发布时间：2018-11-12 09:14

【摘要】：目的:建立国人紫杉醇(paclitaxel,PTX)群体药动学(population pharmacokinetic,PPK)模型,为制定个体化给药方案提供理论支持。方法:收集138例接受紫杉醇治疗的肿瘤患者(建模组105例,验证组33例)210个血样,HPLC法测定紫杉醇血药浓度,PCR-RFLP法检测MDR1 C3435T。应用非线性混合效应模型(NONMEM)法,考察MDR1 C3435T基因多态性、合并用药及病理生理因素对紫杉醇药动学参数的影响,建立紫杉醇PPK模型。对模型进行拟合优度诊断、自举法(Bootstrap)内部验证,正态预测分布误差法(NPDE)及外部验证考察模型预测能力。结果:紫杉醇清除率(CL)和表观分布容积(Vd)的群体典型值分别为64.7 L·h~(-1)和1 240 L,患者内生肌酐清除率(CLcr)和给药速率(RATE)显著影响紫杉醇清除率。最终模型Bootstrap法验证结果与模型计算值相符,拟合优度、准确度及精密度均优于最简模型。结论:紫杉醇PPK最终模型稳定、有效,可结合Bayesian反馈法为临床优化给药方案提供科学依据。
[Abstract]:Aim: to establish a Chinese paclitaxel (paclitaxel,PTX) population pharmacokinetics (population pharmacokinetic,PPK) model to provide theoretical support for the formulation of individualized regimen. Methods: a total of 210 blood samples were collected from 138 patients with tumor treated with paclitaxel (105 patients in model group and 33 patients in validation group). The concentration of paclitaxel was measured by HPLC and MDR1 C3435T by PCR-RFLP. The effects of MDR1 C3435T gene polymorphism, combined drug use and pathophysiological factors on the pharmacokinetic parameters of paclitaxel were investigated by nonlinear mixed effect model (NONMEM). The paclitaxel PPK model was established. The goodness of fit diagnosis, bootstrap (Bootstrap) internal verification, normal prediction distribution error method (NPDE) and external validation are used to evaluate the model prediction ability. Results: the population typical values of paclitaxel clearance rate (CL) and apparent distributed volume (Vd) were 64.7 L h ~ (-1) and 1 240 L, respectively. Endogenous creatinine clearance (CLcr) and administration rate (RATE) significantly affected taxol clearance. The result of the final model Bootstrap method is in agreement with the calculated value of the model, and the goodness of fit, accuracy and precision are better than the simplest model. Conclusion: the final model of paclitaxel PPK is stable and effective. It can provide scientific basis for clinical optimization of drug delivery regimen combined with Bayesian feedback method.
【作者单位】：福建医科大学附属第一医院;厦门市妇幼保健院药学部;
【基金】：福建省卫生系统中青年骨干人才培养计划重点项目(编号:2014-ZQN-ZD-15) 教育部留学回国人员第46批科研启动基金(编号:2013B019)
【分类号】：R969.1

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