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European Journal of Drug Metabolism and Pharmacokinetics

06-05-2024 | Lamotrigine | Original Research Article

Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy

Authors: Jing Yang, Jinxingyi Wang, Lijie Ning, Changsong Wu, Yang Liu, Jie Xia, Yanping Guan, Qian Liu, Jianghuan Zheng

Published in: European Journal of Drug Metabolism and Pharmacokinetics

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Abstract

Background and Objectives

A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy.

Methods

The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence. High-performance liquid chromatography/tandem mass spectrometry was employed to measure the plasma concentrations of lamotrigine. The efficacy of lamotrigine was assessed by evaluating the reduction rate of epileptic seizure frequency.

Results

This study included a cohort of 331 patients who were treated with lamotrigine as monotherapy. A linear correlation was observed between the lamotrigine concentration and daily dose taken (r = 0.58, p < 2.2e−16). Statistically significant differences were found in both the median plasma concentration and dose-adjusted concentration (C/D ratio) when comparing the ineffective to the effective group (p < 0.05). Multivariate analysis showed that UGT1A4 rs2011425, ABCG2 rs2231142 polymorphisms and age had a significant relationship with the lamotrigine concentrations (p < 0.05). Age was a predictive factor for C/D ratio (p < 0.001). Lamotrigine concentration and weight were good predictive factors for effective seizure outcomes (odds ratio [OR] = 0.715, 95% CI 0.658–0.776, p < 0.001; OR = 0.926, 95% CI 0.901–0.951, p < 0.001, respectively). The cut-off values of lamotrigine trough concentrations for clinical outcomes in the age-related groups were determined as 2.49 μg/ml (area under the receiver-operating characteristic curve [AUC]: 0.828, 95% CI 0.690–0.966), 2.70 μg/ml (AUC: 0.805, 95% CI 0.745-0.866) and 3.25 μg/ml (AUC: 0.807, 95% CI 0.686–0.928) for the adult group, adolescent group, and toddler and school-age group, respectively.

Conclusions

UGT1A4 rs2011425 and ABCG2 rs2231142 were correlated with lamotrigine concentrations. Lower lamotrigine trough concentration was found in the ineffective group and the troughs were associated with seizure outcomes.
Appendix
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Literature
1.
Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512–21.CrossRefPubMedPubMedCentral
2.
Leach MJ, Marden CM, Miller AA. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia. 1986;27:490–7.CrossRefPubMed
3.
Rivas N, Buelga DS, Elger CE, Santos-Borbujo J, Otero MJ, Dominguez-Gil A, et al. Population pharmacokinetics of lamotrigine with data from therapeutic drug monitoring in German and Spanish patients with epilepsy. Ther Drug Monit. 2008;30:483–9.CrossRefPubMed
4.
Rowland A, Elliot DJ, Williams JA, MacKenzie PI, Dickinson RG, Miners JO. In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction. Drug Metab Dispos. 2006;34:1055–62.CrossRefPubMed
5.
Blanca Sanchez M, Herranz JL, Leno C, Arteaga R, Oterino A, Valdizan EM, et al. UGT2B7_-161C > T polymorphism is associated with lamotrigine concentration-to-dose ratio in a multivariate study. Ther Drug Monit. 2010;32:177–84.CrossRefPubMed
6.
Chen Y, Xu S, Wang Z, Zhao M, Wang H, Lu T, et al. A population pharmacokinetic-pharmacogenetic model of lamotrigine in Chinese children with epilepsy. Ther Drug Monit. 2018;40:730–7.CrossRefPubMed
7.
Milosheska D, Lorber B, Vovk T, Kastelic M, Dolzan V, Grabnar I. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. Br J Clin Pharmacol. 2016;82:399–411.CrossRefPubMedPubMedCentral
8.
Singkham N, Towanabut S, Lertkachatarn S, Punyawudho B. Influence of the <i>UGT2B7</i> -161C>T polymorphism on the population pharmacokinetics of lamotrigine in Thai patients. Eur J Clin Pharmacol. 2013;69:1285–91.CrossRefPubMed
9.
Ripperger A, Benndorf RA. The C421A (Q141K) polymorphism enhances the 3’-untranslated region (3’-UTR)-dependent regulation of ATP-binding cassette transporter ABCG2. Biochem Pharmacol. 2016;104:139–47.CrossRefPubMed
10.
Ortega-Vazquez A, Fricke-Galindo I, Dorado P, Jung-Cook H, Martinez-Juarez IE, Monroy-Jaramillo N, et al. Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy. Pharmacogenom J. 2020;20:845–56.CrossRef
11.
Motte J, Trevathan E, Arvidsson JFV, Barrera MN, Mullens EL, Manasco P, et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med. 1997;337:1807–12.CrossRefPubMed
12.
Dupouey J, Doudka N, Belo S, Blin O, Guilhaumou R. Simultaneous determination of four antiepileptic drugs in human plasma samples using an ultra-high-performance liquid chromatography tandem mass spectrometry method and its application in therapeutic drug monitoring. Biomed Chromatogr. 2016;30:2053–60.CrossRefPubMed
13.
Wang M-L, Wang H-X, Zhao M-M, Ma Y-Y, Zhao L-M. Redefining the age-specific therapeutic ranges of lamotrigine for patients with epilepsy: a step towards optimizing treatment and increasing cost-effectiveness. Epilepsy Res. 2021;176:106728.CrossRefPubMed
14.
van Dijkman SC, de Jager NCB, Rauwe WM, Danhof M, Della PO. Effect of age-related factors on the pharmacokinetics of lamotrigine and potential implications for maintenance dose optimisation in future clinical trials. Clin Pharmacokinet. 2018;57:1055–6.CrossRefPubMed
15.
Milovanovic JR, Jankovic SM. Population pharmacokinetics of lamotrigine in patients with epilepsy. Int J Clin Pharmacol Ther. 2009;47:752–60.CrossRefPubMed
16.
Mikati MA, Fayad M, Koleilat M, Mounla N, Hussein R, Kazma A, et al. Efficacy, tolerability, and kinetics of lamotrigine in infants. J Pediatr. 2002;141:31–5.CrossRefPubMed
17.
Akman CI, Montenegro MA, Jacob S, Eck K, Chiriboga C, Gilliam F. Seizure frequency in children with epilepsy: factors influencing accuracy and parental awareness. Seizure. 2009;18:524–9.CrossRefPubMed
18.
Morris RG, Black AB, Harris AL, Batty AB, Sallustio BC. Lamotrigine and therapeutic drug monitoring: retrospective survey following the introduction of a routine service. Br J Clin Pharmacol. 1998;46:547–51.CrossRefPubMedPubMedCentral
19.
Froescher W, Uhlmann C. Correlating lamotrigine serum concentration with tolerability in patients with epilepsy. Nerology. 2008;27:446–52.
20.
Zhou J, Argikar UA, Remmel RP. Functional analysis of UGT1A4(P24T) and UGT1A4(L48V) variant enzymes. Pharmacogenomics. 2011;12:1671–9.CrossRefPubMed
21.
Lopez M, Dorado P, Ortega A, Penas-Lledo E, Monroy N, Silva-Zolezzi I, et al. Interethnic differences in UGT1A4 genetic polymorphisms between Mexican Mestizo and Spanish populations. Mol Biol Rep. 2013;40:3187–92.CrossRefPubMed
22.
Cerveny L, Pavek P, Malakova J, Staud F, Fendrich Z. Lack of interactions between breast cancer resistance protein (BCRP/ABCG2) and selected antiepileptic agents. Epilepsia. 2006;47:461–8.CrossRefPubMed
23.
Roemermann K, Helmer R, Loescher W. The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2). Neuropharmacology. 2015;93:7–14.CrossRef
24.
Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug monitoring of antiepileptic drugs in epilepsy: a 2018 update. Ther Drug Monit. 2018;40:526–48.CrossRefPubMed
25.
Gulcebi MI, Ozkaynakci A, Goren MZ, Aker RG, Ozkara C, Onat FY. The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. Epilepsy Res. 2011;95:1–8.CrossRefPubMed
26.
Heyman E, Lavie R, Lahat E, Braunstein R, Bar-Haim A, Berkovitch M, et al. Lamotrigine serum concentration in children with epilepsy. Pediatr Neurol. 2012;47:427–30.CrossRefPubMed
Metadata
Title
Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy
Authors
Jing Yang
Jinxingyi Wang
Lijie Ning
Changsong Wu
Yang Liu
Jie Xia
Yanping Guan
Qian Liu
Jianghuan Zheng
Publication date
06-05-2024
Publisher
Springer International Publishing
Published in
European Journal of Drug Metabolism and Pharmacokinetics
Print ISSN: 0378-7966
Electronic ISSN: 2107-0180
DOI
https://doi.org/10.1007/s13318-024-00894-4