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

Abstract

Abstract Purpose. To estimate whether epilepsy patients with variant UGT2B7 -161C>T(rs7668258) or UGT1A4*3 c.142T>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.142T>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.142T>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.142T>G alleles are equivalent to those in their respective wt peers.