应用群体药动学模型考察联合用药对甲氨蝶呤药动学的影响

发布时间：2018-06-02 14:52

本文选题：儿童 + 甲氨蝶呤　；参考：《中国新药与临床杂志》2017年02期

【摘要】：目的建立儿童甲氨蝶呤(MTX)群体药动学(PPK)模型,考察联合用药对其药动学的影响。方法收集294例急性淋巴细胞白血病(ALL)患儿行大剂量MTX化疗后的血药浓度数据和临床资料。将患儿随机分为两组,模型组(n=245)采用NLME程序进行PPK分析,建立二房室药动学模型,考察各协变量对参数CL_1、CL_2、V_1和V_2的影响。用拟合优度、自举法和正态化预测分布误差对最终模型的性能进行内部验证。采用验证组患儿(n=49)的数据计算平均预测误差(MPE)、平均绝对预测误差(MAE)、平均预测误差平方(MSE)、平方预测误差(SPE)和均方根预测误差(RMSE)对模型进行外部验证。结果最终模型药动学参数的群体典型值为:V_1=20.51 L·m~(-2),V_2=2.95 L·m~(-2),CL_1=6.81 L·m~(-2)·h~(-1),CL_2=0.17 L·m~(-2)·h~(-1)。质子泵抑制剂(PPIs)、青霉素类药物、非甾体抗炎药(NSAIDs)分别使MTX清除率下降20.5%、19.7%、13.1%。其他协变量与MTX清除率无显著相关性。最终模型的预测性能较好且优于基本模型。单用MTX患儿体内MTX清除率高于合用PPIs、青霉素类药物、NSAIDs患儿体内MTX清除率(P0.05)。结论本研究成功建立了ALL患儿MTX化疗后的PPK模型,模型结构表明合用PPIs、青霉素类药物、NSAIDs可使MTX的清除率降低。
[Abstract]:Objective to establish a population pharmacokinetic model of MTX in children and to investigate the effect of combined drug therapy on its pharmacokinetics. Methods Blood drug concentration data and clinical data were collected from 294 children with acute lymphoblastic leukemia (ALL) after high dose MTX chemotherapy. The children were randomly divided into two groups. The model group was analyzed by PPK with NLME program, and the two-chamber pharmacokinetic model was established. The performance of the final model is verified by the goodness of fit, bootstrap method and normal prediction distribution error. The model was verified by using the data of the validation group, such as the mean prediction error (MPEGE), the mean absolute prediction error (mae), the mean prediction error squared (MSE), the square prediction error (SPE) and the root-mean-square prediction error (RMSE). Results the typical population value of pharmacokinetic parameters of the final model was as follows: 1 / V _ 1: 20. 51 L / m ~ (-2) / V _ (2) ~ (2) ~ (95) L ~ (2) L ~ (-1) / L ~ (-1) / L ~ (-1) / L ~ (-1) / L ~ (-1) / L ~ (-1) / L ~ (-1) / L / L / L / L / L / L / L / L / L / L / L / L / L / L / L / L / L Proton pump inhibitor PPP Isa penicillin and NSAIDs reduced the clearance rate of MTX by 20.5 and 19.713.1 respectively. There was no significant correlation between other covariables and MTX clearance. The prediction performance of the final model is better than that of the basic model. The clearance rate of MTX in children with MTX alone was higher than that in children with MTX. The clearance rate of MTX in children with penicillin drugs was higher than that in children with P0. 05%. Conclusion the model of PPK after MTX chemotherapy in children with ALL was successfully established. The structure of the model showed that the clearance rate of MTX could be decreased by penicillin drugs combined with MTX.
【作者单位】：武汉市儿童医院药学部;
【基金】：湖北省卫生厅2011-2012年度科研项目(JX5B74)
【分类号】：R969.1

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