紫杉醇在内蒙地区肿瘤患者中群体药代动力学模型的建立及验证

Population Pharmacokinetic Model of Paclitaxel for Cancer Patients in Inner Mongolia of China

目的建立紫杉醇在内蒙地区肿瘤患者中的群体药代动力学模型,为患者制定精准的个体化给药方案提供参考。方法收集59例接受紫杉醇治疗的肿瘤患者的121个血样,利用免疫比浊法测定紫杉醇血药浓度,采用非线性混合效应模型法(NONMEM)考察年龄、种族、白蛋白等病理生理因素对紫杉醇药动学参数的影响,并建立紫杉醇群体药代动力学模型。对模型进行拟合优度诊断、自举法(Bootstrap)内部验证。结果紫杉醇在内蒙地区肿瘤患者体内的药代动力学符合一室模型,模型的药代动力学参数估计值:清除率0.14 L·h^-1,表观分布容积3.62 L。种族对内蒙地区肿瘤患者的紫杉醇清除率和表观分布容积均有显著影响。结论所建立的群体药代动力学模型稳定,可以较好地反映紫杉醇在内蒙地区肿瘤患者中的群体药代动力学特征,可为临床优化给药方案的制定提供一定的科学依据。

Objective To establish the population pharmacokinetic(PPK)model of paclitaxel for cancer patients in Inner Mongolia of China,providing supports for personalized medication.Methods A total of 121 blood samples were collected from 59 cancer patients treated with paclitaxel.The plasma concentration of paclitaxel was determined by immunonephelometry,and the effects of age,race,albumin and other pathophysiological factors on the pharmacokinetic parameters of paclitaxel were investigated by means of nonlinear mixed effect model(NONMEM)to establish a paclitaxel population pharmacokinetic model.Then the test of goodness of fit and bootstrap internal validation were carried out for the model.The predictive ability of the model was tested through external validation.Results A two-compartment model provided the best fit for paclitaxel.Typical value of clearance and the apparent volume of distribution were 0.14 L·h^-1 and 3.62 L respectively.The clearance and the volume of distribution were significantly associated with the race.Conclusions The population pharmacokinetic final model is stable and effective.It can fit the population pharmacokinetics characteristic of paclitaxel for cancer patients in Inner Mongolia of China.And it may provide a scientific basis for clinical optimization of drug delivery scheme.