A Population Pharmacokinetic-Pharmacogenetic Model of Lamotrigine in Chinese Children With Epilepsy.

BACKGROUND: The pharmacokinetics of lamotrigine (LTG) is complex and varies significantly among individuals, especially among children. Therefore, this study aimed to establish a population pharmacokinetic (PPK) model of LTG in Chinese children with epilepsy and to comprehensively evaluate the effects of genetic variations in drug-metabolizing enzymes, transporters, and a transcriptional regulator on LTG pharmacokinetics.

METHODS: Three hundred eighty-five steady-state plasma concentrations were obtained from 179 children (age 10.72 ± 3.05 years and body weight 46.23 ± 17.77 kg) with epilepsy during therapeutic drug monitoring. These patients were divided into the PPK-model group (n = 121) and the PPK-validation group (n = 58) and were genotyped for UGT1A4, UGT2B7, ABCB1, ABCG2, SLC22A1, and HNF4α. PPK analysis was performed by nonlinear mixed effects modeling.

RESULTS: In the final model, apparent clearance (CL/F) of LTG was estimated to be 1.48 L/h; 500 mg valproic acid, oxcarbazepine, and UGT2B7-161TT genotype changed the CL/F by -46.2, +31.1, and -21.8%, respectively. Body weight was also identified as a significant covariate affecting LTG CL/F.

CONCLUSIONS: A PPK-pharmacogenetic model of LTG in Chinese children with epilepsy was successfully established with nonlinear mixed effects modeling. Genotyping for UGT2B7-161C>T may be useful in titrating the optimal LTG dose.