Secondary Logo

Institutional members access full text with Ovid®

Share this article on:

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: lmzhao19@163.com).

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.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com).

Received April 30, 2018

Accepted July 03, 2018

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