Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy

Abstract

Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.

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Fig. 1: Analysis of UGT1A4 variants.
Fig. 2: Box and whiskers (min. to max.) plots of lamotrigine (LTG) plasma concentration.

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Acknowledgements

We are grateful for support from the Consejo Nacional de Ciencia y Tecnología (CONACYT) of Mexico grant #167261. This study was coordinated by RIBEF network (Red Iberoamericana de Farmacogenética y Farmacogenómica; www.ribef.com).

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Ortega-Vázquez, A., Fricke-Galindo, I., Dorado, P. et al. Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy. Pharmacogenomics J (2020). https://doi.org/10.1038/s41397-020-0173-2

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