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Front. Pharmacol. | doi: 10.3389/fphar.2019.00832

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: a Prospective Analysis in Chinese Patients with Epilepsy

Zhan-zhang Wang1, 2, Yue-feng Zhang3, Wen-can Huang4, Xi-pei Wang5, Xiao-jia Ni1, Hao-yang Lu1, Jin-qing Hu1, Shu-hua Deng1, Xiu-qing Zhu1, Huan-shan Xie1, Hong-zhen Chen1, Ming Zhang1, Chang Qiu1, Yu-guan Wen1, 2* and  De-wei Shang1, 2*
  • 1Department of Pharmacy, Guangzhou Brain Hospital, Guangzhou Medical University, China
  • 2Other, China
  • 3Department of Neurology, Guangzhou Brain Hospital, Guangzhou Medical University, China
  • 4Guangzhou Civil Affairs Bureau Mental Hospital, China
  • 5Guangzhou Institute of Cardiovascular Disease, China

1. Abstract
Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT)1A4, UGT2B7, MDR1, ABCG2, ABCC2 and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.11 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1-1222AA carriers. Patients with the ABCG2-34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1-2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13–65 years of age.

Keywords: Lamotrigine (LTG), NONMEM, population pharmacodynamics, Epilepsy, Chinese

Received: 01 Apr 2019; Accepted: 28 Jun 2019.

Edited by:

Ke-Vin Chang, National Taiwan University Hospital, Taiwan

Reviewed by:

Karel Allegaert, University Hospitals Leuven, Belgium
Hea-young Cho, CHA University, South Korea  

Copyright: © 2019 Wang, Zhang, Huang, Wang, Ni, Lu, Hu, Deng, Zhu, Xie, Chen, Zhang, Qiu, Wen and Shang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Yu-guan Wen, Department of Pharmacy, Guangzhou Brain Hospital, Guangzhou Medical University, Guangzhou, China,
Dr. De-wei Shang, Department of Pharmacy, Guangzhou Brain Hospital, Guangzhou Medical University, Guangzhou, China,