AIM: To establish a population pharmacokinetic/pharmacodynamic (PK/PD) model for valproate (VPA) in children with epilepsy in China, and promote reasonable use of antiepileptic drug in clinical practice. METHODS: Spar...AIM: To establish a population pharmacokinetic/pharmacodynamic (PK/PD) model for valproate (VPA) in children with epilepsy in China, and promote reasonable use of antiepileptic drug in clinical practice. METHODS: Sparse data of VPA serum concentrations from 417 pediatric children were collected. These patients were divided into three groups: Population PK-Index group, n=317; Population PK-Valid group, n=100; 115 of the total 417 subjects were also included in the Population PD group. Population PK parameters of VPA were estimated based on the data from population PK-Index group. In the validation procedure, the serum concentrations of VPA from the population PK-Valid group were predicted by base and final models respectively. To assess the accuracy and precision of the predictions, mean prediction error (MPE), mean squared prediction error (MSPE), root mean squared prediction error (RMSPE), weight-residues (WRES) and its 95% confidence intervals (95%CI) were all calculated, then compared between the two models. For population PD group, all of the 115 patients were VPA monotherapy. Efficacy of epilepsy treatment was divided into 5 grades according to the percentage of seizure frequency decreased (PSFD%). The value of PSFD% 100%, 75%-100%, 50%-75%, 25%-50%, or less than 25% are corresponding to grade 1 to 5. For population PD group, the quantitative relationship between the VPA serum concentrations and the probability for its efficacy score was characterized by logistic regression. RESULTS: Population PK of VPA was described by one-compartment model with first order absorption. In the final model, Ka, V/F, CL/F are 0.251+2.24·(1-HS) (/h), 2.88+0.157·WT (L), 0.1060.98·CO+0.0157·AGE (L/h), respectively. The final model was validated internally and externally. Logistic regression showed that VPA serum concentrations and corresponding peak probability for its efficacy were (25 μg/mL, grade 5, 50%), (32 μg/mL, grade 4, 32.3%), (50 μg/mL, grade 3, 26.3%), (67 μg/mL, grade 2, 36.5%), and (78 μg/mL, grade 1, 50%), respectively. CONCLUSION: The population PK/PD model of VPA in children with epilepsy in China is successfully established by NONMEM, and the probability of efficacy for a given concentration is satisfactorily estimated as well.展开更多
目的通过非线性混合效应模型(NONMEM)法建立癫患儿丙戊酸群体药动学模型,为制定个体化给药方案提供依据。方法收集2004至2008年在复旦大学附属儿科医院住院并应用丙戊酸常规治疗的癫患儿的临床资料,包括血药浓度数据、生理指标及与...目的通过非线性混合效应模型(NONMEM)法建立癫患儿丙戊酸群体药动学模型,为制定个体化给药方案提供依据。方法收集2004至2008年在复旦大学附属儿科医院住院并应用丙戊酸常规治疗的癫患儿的临床资料,包括血药浓度数据、生理指标及与其他抗癫药联合用药情况。采用NONMEM法建立丙戊酸群体药动学模型,采用一级吸收和消除的一房室模型拟合丙戊酸的药动学过程,吸收速率常数固定为1.9.h-1,个体间变异用对数模型,采用个体间变异和残差变异有交互作用的一级速率条件算法计算。考察生理和联合用药对表观分布容积(V/F)和相对清除率(CL/F)的影响。模型验证采用200次bootstrap法。结果纳入癫患儿321例,收集血药浓度数据点390个,每例患儿采样1～5个。丙戊酸单药治疗115/321例(35.8%),与其他抗癫药合用206/321例(64.2%)。年龄中位数为1.8(0.1～13.6)岁,体重中位数为11.5(2.6～84)kg,丙戊酸剂量为30.8(4.8～88.9)mg.d-1.kg-1。患儿年龄,与氯硝西泮、卡马西平或苯巴比妥合用均是丙戊酸CL/F的影响因素。模型的参数为:CL/F=0.223.(Age/1.8)0.353.1.22CLO.1.36LEI,V/F=13.0.(Total body weight/11.5);与氯硝西泮合用,CLO=1,否则为0;与卡马西平或苯巴比妥合用,LEI=1,否则为0。与氯硝西泮合用可增加丙戊酸CL/F约22%,与卡马西平或苯巴比妥合用可增加丙戊酸CL/F约36%。最终模型较基本模型可降低CL/F的个体间变异(34.3%vs51.5%)。Bootstrap法的验证结果与模型计算值相符。结论建立的丙戊酸群体药动学模型有一定代表性,可为采用Bayesian法进行个体化给药奠定基础。展开更多
文摘AIM: To establish a population pharmacokinetic/pharmacodynamic (PK/PD) model for valproate (VPA) in children with epilepsy in China, and promote reasonable use of antiepileptic drug in clinical practice. METHODS: Sparse data of VPA serum concentrations from 417 pediatric children were collected. These patients were divided into three groups: Population PK-Index group, n=317; Population PK-Valid group, n=100; 115 of the total 417 subjects were also included in the Population PD group. Population PK parameters of VPA were estimated based on the data from population PK-Index group. In the validation procedure, the serum concentrations of VPA from the population PK-Valid group were predicted by base and final models respectively. To assess the accuracy and precision of the predictions, mean prediction error (MPE), mean squared prediction error (MSPE), root mean squared prediction error (RMSPE), weight-residues (WRES) and its 95% confidence intervals (95%CI) were all calculated, then compared between the two models. For population PD group, all of the 115 patients were VPA monotherapy. Efficacy of epilepsy treatment was divided into 5 grades according to the percentage of seizure frequency decreased (PSFD%). The value of PSFD% 100%, 75%-100%, 50%-75%, 25%-50%, or less than 25% are corresponding to grade 1 to 5. For population PD group, the quantitative relationship between the VPA serum concentrations and the probability for its efficacy score was characterized by logistic regression. RESULTS: Population PK of VPA was described by one-compartment model with first order absorption. In the final model, Ka, V/F, CL/F are 0.251+2.24·(1-HS) (/h), 2.88+0.157·WT (L), 0.1060.98·CO+0.0157·AGE (L/h), respectively. The final model was validated internally and externally. Logistic regression showed that VPA serum concentrations and corresponding peak probability for its efficacy were (25 μg/mL, grade 5, 50%), (32 μg/mL, grade 4, 32.3%), (50 μg/mL, grade 3, 26.3%), (67 μg/mL, grade 2, 36.5%), and (78 μg/mL, grade 1, 50%), respectively. CONCLUSION: The population PK/PD model of VPA in children with epilepsy in China is successfully established by NONMEM, and the probability of efficacy for a given concentration is satisfactorily estimated as well.
文摘目的通过非线性混合效应模型(NONMEM)法建立癫患儿丙戊酸群体药动学模型,为制定个体化给药方案提供依据。方法收集2004至2008年在复旦大学附属儿科医院住院并应用丙戊酸常规治疗的癫患儿的临床资料,包括血药浓度数据、生理指标及与其他抗癫药联合用药情况。采用NONMEM法建立丙戊酸群体药动学模型,采用一级吸收和消除的一房室模型拟合丙戊酸的药动学过程,吸收速率常数固定为1.9.h-1,个体间变异用对数模型,采用个体间变异和残差变异有交互作用的一级速率条件算法计算。考察生理和联合用药对表观分布容积(V/F)和相对清除率(CL/F)的影响。模型验证采用200次bootstrap法。结果纳入癫患儿321例,收集血药浓度数据点390个,每例患儿采样1～5个。丙戊酸单药治疗115/321例(35.8%),与其他抗癫药合用206/321例(64.2%)。年龄中位数为1.8(0.1～13.6)岁,体重中位数为11.5(2.6～84)kg,丙戊酸剂量为30.8(4.8～88.9)mg.d-1.kg-1。患儿年龄,与氯硝西泮、卡马西平或苯巴比妥合用均是丙戊酸CL/F的影响因素。模型的参数为:CL/F=0.223.(Age/1.8)0.353.1.22CLO.1.36LEI,V/F=13.0.(Total body weight/11.5);与氯硝西泮合用,CLO=1,否则为0;与卡马西平或苯巴比妥合用,LEI=1,否则为0。与氯硝西泮合用可增加丙戊酸CL/F约22%,与卡马西平或苯巴比妥合用可增加丙戊酸CL/F约36%。最终模型较基本模型可降低CL/F的个体间变异(34.3%vs51.5%)。Bootstrap法的验证结果与模型计算值相符。结论建立的丙戊酸群体药动学模型有一定代表性,可为采用Bayesian法进行个体化给药奠定基础。
