Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy.

Ming Zhang,Wen-Can Huang,De-Wei Shang,Xiu-Qing Zhu,Yu-Guan Wen,Chang Qiu,Hong-Zhen Chen,Jin-Qing Hu,Hao-Yang Lu,Xi-Pei Wang,Huan-Shan Xie,Shu-Hua Deng,Xiao-Jiao Ni,Yue-Feng Zhang,Zhan-Zhang Wang

doi:10.3389/fphar.2019.00832

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 1.12 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.

Highlights

Lamotrigine (LTG), a second-generation anti-epileptic drug belonging to the phenyltriazine family, has been widely used for treating focal and generalized seizures and bipolar disorder type I in adults and children, either as a monotherapy (>12 years) or in combination with other anti-epileptic drugs (AEDs) (>2 years) (He et al, 2012)
The frequencies of the wildtype allele for UGT1A4 and UGT2B7 were higher than 48.3%, whereas the homozygous allele frequency was lower than 10.1%, in agreement with the frequencies previously reported in the Chinese population (Liu et al, 2015; Wang et al, 2015; Li et al, 2018)
No patients with the UGT1A470C > A mutation were found in the current study, which results similar to those in other studies on Asian [Japanese (Saeki et al, 2005) and Thai (Singkham et al, 2013)] populations

Summary

INTRODUCTION

Lamotrigine (LTG), a second-generation anti-epileptic drug belonging to the phenyltriazine family, has been widely used for treating focal and generalized seizures and bipolar disorder type I in adults and children, either as a monotherapy (>12 years) or in combination with other anti-epileptic drugs (AEDs) (>2 years) (He et al, 2012). In the one study on Chinese patients with epilepsy, a statistically significant association between SLC22A1 rs628031 polymorphism and normalized LTG concentration has been observed (Shen et al, 2016). One study in Caucasian adult patients has investigated the effects of genetic polymorphisms of SLC22A1, UGT2B7, UGT1A4, and ABCB1 on LTG concentration and has included UGT2B7 polymorphisms, coadministration of enzyme inducers, smoking status, and body weight in the final model (Milosheska et al, 2016). Two population pharmacokinetic (PPK) LTG studies have been conducted to identify non-genetic factors in Chinese children (Liu et al, 2015; Zhang et al, 2017), the identification and quantification of genetic polymorphisms in Chinese children and adults, especially with complicated comedication with enzyme modifiers in real-world therapy, are still lacking. The population predictions of LTG concentrations are shown for each simulation scenario

RESULTS

DISCUSSION

CONCLUSION

ETHICS STATEMENT