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

Chen, Yanan, PhD*; Xu, Shansen, PhD*; Wang, Zhanyou, PhD; Zhao, Mingming, MD*; Wang, Huanxin, MD*; Lu, Tong, MD; Zhao, Limei, PhD*

doi: 10.1097/FTD.0000000000000563
Original Article

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.

*Department of Pharmacy, Shengjing Hospital of China Medical University;

Key Laboratory of Medical Cell Biology of Ministry of Education, Institute of Health Sciences, China Medical University; and

School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.

Correspondence: Limei Zhao, PhD, Department of Pharmacy, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, Liaoning, China (e-mail:

Supported by grants from the National Natural Science Foundation of China (No. 81673510, No. U1608282, and No. 81703628).

The authors declare no conflict of interest.

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Received April 30, 2018

Accepted July 03, 2018

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.