癫癎儿童拉莫三嗪的群体药代动力学研究

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

摘要:

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1.16 L/h(0.042 L/h?kg)、40.2 L(1.46 L/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。

Abstract:

OBJECTIVE: To establish a population pharmacokinetics (PPK) model of lamotrigine, an antiepileptic drug, in Chinese children with epilepsy to formulate an individualized dosage guideline. METHODS: A total of 303 data, including the random ones of serum lamotrigine concentrations from 165 epileptic children were analyzed. Lamotrigine concentrations were determined by the RP-HPLC method. PPK model of lamotrigine was established using NONMEM, a population pharmacokinetic computer program, according to one-compartment model with first-order absorption and elimination. To evaluate the accuracy and precision of predicting lamotrigine concentrations, mean error (ME), mean squared prediction error (MSE), standard mean squared prediction error (SME), root mean squared prediction error (RSME), WRES and their 95% confidence interval were calculated in both the base and the final models. RESULTS: Regression equation of the base model of lamotrigine was obtained, ie, clearance (CL/F)=0.664×EXP［ETA(1)］, volume of distribution (V/F)=45×EXP［ETA(2)］, and KA=4.0×EXP ［ETA(3)］, and that of the final model was as follows: 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)］. The population values of 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 for lamotrigine respectively in the final model. The final PPK model was demonstrated to be stable and effective in the prediction of serum lamotrigine concentrations by internal and external approaches validation. CONCLUSIONS: A PPK model of lamotrigine in Chinese children with epilepsy was successfully established using NONMEM. Lamotrigine concentrations can be predicted accurately by the model. The model may be helpful to reasonable use of antiepileptic drugs in clinical practice.