title: Population pharmacokinetic models of lamotrigine in different age groups of Chinese children with epilepsy.
abstract: OBJECTIVE
  The study aims to establish population pharmacokinetic (PPK) models of lamotrigine (LTG) in different age groups of epileptic children by nonlinear mixed effect modelling(NONMEM), and provide essential tools and theoretical basis for individualised optimal drug dose.
  
  
  METHODS
  Cases of 473 epileptic children were divided into infant, toddler and preschool age (≤6 years) (n = 211), school age (6-12 years) (n = 171) and adolescence age (>12 years) (n = 81). A total of 625 steady-state serum trough concentration samples were extracted. The clinical information included demography, medication, serum concentration data and blood biochemical parameters. PPK models of LTG were established by NONMEM program, using first-order absorption and elimination. Demography and drug combination was investigated for influence on apparent clearance (CL) and apparent volume of distribution (Vd). To assess the accuracy and precision of the different ages and whole-age model, the mean prediction error (MPE), mean absolute error (MAE) and root mean squared error (RMSE) were compared.
  
  
  RESULTS
  The final model of LTG in different ages stage and whole age was as follows: (1) infant, toddler and preschool age CL = 0.715 × [(WEIG/16.25)0.655] × (0.458VPA) × (1.99IND), V = 10.4; (2) school age CL(L/h) = 1.01 × (WEIG/30)0.399× 0.465VPA× 1.98IND, Vd(L) = 17.7; (3) adolescence age CL(L/h) = 1.49 × (WEIG/51.5)0.509× 0.498VPA× 1.7IND, Vd(L) = 23.1; (4) whole age CL = 0.945 × [(WEIG/25)0.645] × (0.463VPA) × (1.94IND), V = 16.7 × (WEIG/25)0.919(WEIG, total body weight; VPA, combination with valproate, yes = 1, no = 0; IND, combination with enzyme inducer, yes = 1, no = 0). The values of MPE, MAE and RMSE in age-stage-specific models were less than the ones in the whole-age model, which suggests the age-stage-specific models have better precision and accuracy than the whole-age model.
  
  
  CONCLUSIONS
  PPK models of LTG in different age groups of epileptic children were successfully established. Weight and combination therapy were identified as significant covariates on LTG clearance. Compared with the whole-age model, the age-specific models are more reliable.
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China.
authors.forename: Zhong-Bin
authors.initials: ZB
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Peking University, No.38 Xueyuan Road, Haidian District, Beijing, 100191, China.
authors.forename: Shuang-Min
authors.initials: SM
authors.lastname: Ji
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China.
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Peking University, No.38 Xueyuan Road, Haidian District, Beijing, 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China. dryewu@263.net.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000927:Anticonvulsants / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002681:China; D006801:Humans; D007223:Infant; D000077213:Lamotrigine; D014227:Triazines / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine
keywords: Chinese children; Epilepsy; Lamotrigine; Population pharmacokinetics