Bearing variant alleles at uridine glucuronosyltransferase polymorphisms UGT2B7 -161C > T (rs7668258) or UGT1A4*3 c.142 T > G (rs2011425) has no relevant consequences for lamotrigine troughs in adults with epilepsy

Scientific paper - Original scientific paper

• Author: Nada Božina
• Author: Ivana Šušak Sporiš
• Author: Iva Klarica Domjanović
• Author: Lana Ganoci
• Author: Livija Šimičević
• Author: Mila Lovrić
• Author: Zrinka Čolak Romić
• Author: Željka Petelin Gadže
• Author: Vladimir Trkulja
• Author's institution: University of Zagreb; School of Medicine; (Department of Pharmacology)
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Pharmacology

Abstract (english)

Purpose: To estimate whether epilepsy patients with variant UGT2B7 -161C > T (rs7668258) or UGT1A4*3 c.142 T > G (rs2011425) alleles differ from their wild-type (wt) peers in exposure to lamotrigine.

Methods: Consecutive adults on lamotrigine monotherapy or lamotrigine + valproate co-treatment undergoing routine therapeutic drug monitoring, otherwise generally healthy and free of interacting drugs, were genotyped for UGT2B7 -161C > T and UGT1A4*3 c.142 T > G. Heterozygous, variant homozygous, or combined heterozygous/variant homozygous subjects were compared to their wt controls for dose-adjusted lamotrigine troughs with adjustment for age, sex, body weight, rs7668258/rs2011425, polymorphisms of efflux transporter proteins ABCG2 c.421C > A (rs2231142) and ABCB1 1236C > T (rs1128503), and level of exposure to valproate using covariate entropy balancing.

Results: Of the 471 included patients, 328 (69.6%) were on monotherapy and 143 were co-treated with valproate. Dose-adjusted lamotrigine troughs in UGT2B7 -161C > T heterozygous (CT, n = 237) or variant homozygous (TT, n = 115) subjects were closely similar to those in their wt controls (CC, n = 119): geometric means ratios (GMRs) (frequentist and Bayes) 1.00 (95%CI 0.86-1.16) and 1.00 (95%CrI 0.83-1.22) for CT vs. CC; and 0.97 (0.81-1.17) and 0.97 (0.80-1.20) for TT vs. CC subjects. Lamotrigine troughs were also closely similar in UGT1A4*3 c.142 T > G variant carriers (n = 106: 102 TG + 4 GG subjects) and wt controls (TT, n = 365): GMR = 0.95 (0.81-1.12) frequentist, 0.96 (0.80-1.16) Bayes. GMRs for variant carriers vs. wt controls were around unity also at different levels of exposure to valproate.

Conclusion: Dose-adjusted lamotrigine troughs in epilepsy patients with variant UGT2B7 -161C > T or UGT1A4*3 c.142 T > G alleles are equivalent to those in their respective wt peers.

• Keywords (english): Bioavailability; Lamotrigine; Polymorphism; Uridine glucuronosyltransferases (UGTs)
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Accepted version
• Journal title: European Journal of Clinical Pharmacology
• Numbering: vol. 79, no. 8, pp. 1117-1129
• p-ISSN: 0031-6970
• e-ISSN: 1432-1041
• DOI: https://doi.org/10.1007/s00228-023-03526-z
• URN:NBN: urn:nbn:hr:105:062920
• Publication: 2023-08
• Document URL: https://link.springer.com/10.1007/s00228-023-03526-z
• Type of resource: Text
• Access conditions: Open access; Embargo expiration date: 2024-09-01
• Created on: 2023-10-02 09:16:15