Establishment of population pharmacokinetic models with valproic acid in different age groups of Chinese epileptic children

Abstract

Objective To establish population pharmacokinetic (PPK) models with valproic acid(VPA) in different age groups(infant and toddler, preschool age, school age and adolescence) of Chinese epileptic children by nonlinear mixed effect modeling(NONMEM), and provide evidence for individualized drug therapy. Methods Cases of 518 epileptic children were collected from 2010 to 2013 in the Pediatric Outpatient Clinics of the First Hospital, Peking University.The clinical information included demographic data, medication, serum concentration data and blood biochemical parameters.The patients were divided into infants and toddlers (n=191), children at preschool age(n=172) and children at school and adolescence age(n=155). A total of 665 steady-state serum trough concentration samples were extracted.Population pharmacokinetic models of VPA were established by NONMEM program by using first-order absorption and elimination.Demography and drug combination was investigated for influence on apparent clearance (CL/F) and apparent volume of distribution (V/F). The reliability and stability of the PPK models were evaluated by 1 000 times of Bootstrap procedure.To assess the accuracy and precision of the different age groups models and whole age model, the average prediction error (MPE), average absolute error (MAE) and average root variance (RMSE) were compared. Results The final model of VPA in different age groups and whole age group were: 1.the infant and toddler's age group CL/F(L/h)=0.154×(WEIG/11.5)1.31, V/F(L)=3.32×(WEIG/11.5)2.49. 2.preschool age group CL/F(L/h)=0.211×(WEIG/18)0.534, V/F(L)=4.08. 3.school and adolescence age group CL/F(L/h)=0.287×(WEIG/29.75)0.464, V/F(L)=7.05. 4.whole age group CL/F(L/h)=0.197×(WEIG/18)0.648×1.09GEND, V/F(L)=4.25×(WEIG/18)0.714(GEND was gender, male=1, female=0; WEIG was weight). The results of Bootstrap procedure were corresponding to the estimates from NONMEM.The values of the different age groups model MPE, MAE, RMSE were less than ones of the whole age group, which suggested the different age groups models had better precision and accuracy than the whole age group models. Conclusions PPK models of VPA in different age groups of Chinese epileptic children by NONMEM were successfully established.Weight was identified as a significant cova－riate on VPA clearance.Compared with the whole age group models，the different age groups models are more reliable. Key words: Valproic acid; Population pharmacokinetics; Epilepsy; Different age groups