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目的用NONMEM软件建立中国癫癎儿童拉莫三嗪(LTG)的群体药代动力学(PPK)模型。方法回顾性收集服用LTG的癫癎165名患儿的303份血样浓度数据及临床资料,血药浓度为临床常规监测的稳态浓度,采用反相高效液相色谱法测定。应用PPK专业软件NONMEM,按照一室一级吸收和消除模型,建立我国癫癎儿童LTG的PPK模型。用平均预测误差(ME)、标准平均预测误差(SME)、平均方差(MSE)、平均根方差(RMSE)及加权残差(WRES)作为模型预测准确程度和精密程度的评价指标,对基础模型和最终模型的预测效能进行比较。结果LTG的基础模型为:CL/F=0.664×EXP[ETA(1)],V/F=45×EXP[ETA(2)],KA=4.0×EXP[ETA(3)];最终回归模型为:CL/F=0.717×(1-0.601×VPA)×(1+1.18×EI)×[1.62∧(AGE/7.02)]×EXP[ETA(1)],V/F=40.2×EXP[ETA(2)],KA=3.27×EXP[ETA(3)]。CL/F、V/F、KA的群体典型值分别为1.16L/h(0.042L/h·kg)、40.2L(1.46L/kg)和3.27/h。经过内部验证和外部验证,所建立的最终模型有良好的稳定性和预测效能。结论应用NONMEM软件成功地建立了我国癫癎儿童LTG的PPK模型,可准确的预测LTG血药浓度,促进了个体化给药方案的实施。
Objective To establish a population pharmacokinetic (PPK) model of lamotrigine (LTG) for epileptic children in China with NONMEM software. Methods A total of 303 blood samples were collected from 165 epileptic patients taking LTG and their clinical data were collected. The plasma concentration was the steady-state concentration routinely monitored by RP-HPLC. Application PPK professional software NONMEM, according to a one-compartment absorption and elimination model, the establishment of China’s epilepsy children LTG PPK model. ME, SME, MSE, RMSE and WRES were used as evaluation indexes to predict the accuracy and precision of the model. The basic model The predicted performance of the final model is compared. Results The basic models for LTG were: CL / F = 0.664 × EXP [ETA (1)], V / F = 45 × EXP [ETA (2)], KA = 4.0 × EXP [ETA Is: CL / F = 0.717 × 1-0.601 × VPA × 1 + 1.18 × EI × 1.62∧ AGE / 7.02 × EXP [ETA (1)], V / F = 40.2 × EXP [ ETA (2)], KA = 3.27 × EXP [ETA (3)]. Typical population values for CL / F, V / F and KA were 1.16 L / h (0.042 L / h · kg), 40.2 L (1.46 L / kg) and 3.27 / h, respectively. After internal verification and external verification, the final model established has good stability and predictive performance. Conclusion The PPK model of LTG in children with epilepsy was established successfully by NONMEM software, which can accurately predict the concentration of LTG and promote the implementation of individualized dosing regimen.