用NONMEM法建立中国癫痫儿童丙戊酸钠的群体药动学/药效学结合模型  

Setting up population pharmacokinetics/pharmacodynamics model of VPA in children with epilepsy by NONMEM software

作　　者：姜德春[1] 王丽[1] 卢炜[2] 

机构地区：[1]北京大学第一医院儿科 [2]北京大学药学院,北京100034

出　　处：《中国临床药理学与治疗学》2005年第11期1279-1285,共7页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：国家自然科学基金资助项目(№30440076)

摘　　要：目的:建立中国癫痫儿童应用丙戊酸钠(VPA)的群体药动学药效学(PPKPD)结合模型,为设计个体化用药方案奠定基础。方法:回顾性收集246例癫痫患儿应用VPA的临床数据。血药浓度是常规监测的稳态浓度。用246例患儿的数据,通过NONMEM法已经自行成功建立PPK模型。现将246例中单用VPA的69例的数据与已经建立的PPK模型结合,建立PPKPD模型。药效指标用癫痫发作次数减少百分比,分为5级。应用Logistic回归分析,拟合线性药效模型,用NONMEM法建立PPKPD模型,求算血药浓度获得某一级疗效的概率。结果:应用Logistic回归分析,拟合线性药效模型,求算出血药浓度获得某一级疗效的概率:血药浓度超过23μg·ml-1时,5级的概率小于50%,获得4、3、2级的最大概率及浓度为(30μg·ml-1,32.3%)、(50μg·ml-1,26.3%)、(65μg·ml-1,36.5%);血药浓度超过78μg·ml-1时,1级的概率大于50%;浓度为100μg·ml-1时,1级的概率约84.2%。结论:用NONMEM法成功地建立了中国癫痫儿童应用VPA的PPKPD模型,定量地求出某一血药浓度获得不同疗效等级的概率。AIM： To set up population pharmacokinetie/phannaeodynamics （PPK/PD） model of valproate （VPA） in children with epilepsy in China, and promote reasonable use of antiepileptic drugs （AEDs）in clinical praetice. METHODS： Sparse data of VPA serum concentrations from 246 pediatric children were collected. These patients were divided into three groups： PPK-Model group （ n = 146）, to calculate PPK parameter values of VPA and set up a PPK model; PPK-Valid group （n = 100）, to valid the PPK model; and PPD group （n = 69）, to set up PPK/PD model. Based on the data of PPK-Model group and PPK-Valid group, a PPK model of VPA in children with epilepsy in China was successfully set up by using NONMEM software by ourselves. Now, using the data of 69 patients in PP1） group who were on VPA monotherapy and this PPK model, we set up PPK/ PD model by NONMEM software, Efficacy of epilepsy treatment was divided into 5 grades according to the pereentage of seizure frequency decreased （ PSFD% ） ： grade 1： PSFD% was 100%; grade 2： PSFD% was 75% -100% ; grade 3： PSFD% was 50% - 75% ; grade 4： PSFD% was 25% -50%; grade 5： PSFD% was less than 25%. The quantitive relationship between the VPA serum concentrations and the probability for its efficacy score was characterized by Logistic regression analysis with NONMEM. RESULTS： Logistic regression analysis showed that, VPA serum concentrations and the probability for its efficacy grades 5, 4, 3, 2, and 1 were （23 μg·ml^-1, 5, 50%）, （30μg·ml^-1, 4, 32.3%）, （50 μg·ml^-1, 3, 26.3%）, （65 μg·ml^-1, 2, 36.5%）, （78μg·ml^-1, 1, 50%）, and （100 μg·ml^-1, 1, 84.2% ） respectively. CONCLUSION： A PPK/PD model of VPA in children with epilepsy in China is successfully established by using NONMEM software, and the probability of efficacy grade for any concentration can be calculated. It will be valuable to facilitate individualized dosage regimen.

关 键 词：癫痫 儿童 丙戊酸钠 群体药动学 群体药效学 NONMEM法 

分 类 号：R969.1[医药卫生—药理学]