Population pharmacokinetic models of lamotrigine in different age groups of Chinese children with epilepsy

• Published in: European journal of clinical pharmacology 2017-04, Vol.73 (4), p.445-453
• Main Authors: Zhang, Zhong-bin, Ji, Shuang-min, Han, Ying, Zang, Li-li, Wang, Ying-hui, Lu, Wei, Wang, Li, Wu, Ye
• Format: Article
• Language: English
• Subjects: Anticonvulsants - pharmacokinetics; Biomedical and Life Sciences; Biomedicine; Child; Child, Preschool; Children & youth; China; Epilepsy; Humans; Infant; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Triazines - pharmacokinetics
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-016-2190-2

Purpose 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 ( V d). 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 ] × (0.458 VPA ) × (1.99 IND ), V  = 10.4; (2) school age CL(L/h) = 1.01 × (WEIG/30) 0.399  × 0.465 VPA  × 1.98 IND , V d(L) = 17.7; (3) adolescence age CL(L/h) = 1.49 × (WEIG/51.5) 0.509  × 0.498 VPA  × 1.7 IND , V d(L) = 23.1; (4) whole age CL = 0.945 × [(WEIG/25) 0.645 ] × (0.463 VPA ) × (1.94 IND ), 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. Conclusion 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.