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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

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Abstract

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.

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Data availability

Data can be obtained upon a reasonable request from the corresponding author.

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Acknowledgements

We thank Zrinka Mirković and Maja Mezak Herceg for their technical support.

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Contributions

All authors were fully involved in manuscript development and assume responsibility for the direction and content. N.B.,VT., IŠS., I.K.D., conceived the study. M.L., L.G.,L.Š. and N.B. performed and reviewed the bioanalytical analyses. V.T. performed data analysis and drafted the manuscript. N.B., V.T., I.Š.S., I.K.D.,M.L., Z.Č.R. Ž.P.G. participated in the preparation of the manuscript. All authors reviewed the manuscript and provided their approval for submission.

Corresponding author

Correspondence to Vladimir Trkulja.

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This study was approved by the Ethics Committee at the Zagreb University Hospital Center (approval class: 8.1.-19/12–2, registration number: 02/21/AG).

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Božina, N., Sporiš, I.Š., Domjanović, I.K. et al. 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. Eur J Clin Pharmacol 79, 1117–1129 (2023). https://doi.org/10.1007/s00228-023-03526-z

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