Breast cancer resistance protein polymorphism ABCG2 c.421C>A (rs2231142) moderates the effect of valproate on lamotrigine trough concentrations in adults with epilepsy

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology Pub Date : 2023-10-04 DOI:10.1111/fcp.12958

Ivana Šušak Sporiš, Nada Božina, Iva Klarica Domjanović, Davor Sporiš, Silvio Bašić, Ivana Bašić, Mila Lovrić, Lana Ganoci, Vladimir Trkulja

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引用次数: 0

Abstract

Background

Valproate inhibits clearance of lamotrigine and greatly increases its concentrations. We assessed whether this effect was moderated by a polymorphism (ABCG2 c.421C>A) of the breast cancer resistance protein.

Methods

In two consecutive independent studies in adults with epilepsy on lamotrigine monotherapy or cotreated with valproate: (i) Exposure to valproate was considered treatment, (ii) dose-adjusted lamotrigine troughs at steady state were the outcome, and (iii) ABCG2 c.421C>A genotype (wild-type [wt] homozygosity or variant carriage) was the tested moderator. We used entropy balancing (primary analysis) and exact/optimal full matching (secondary analysis) to control for confounding, including polymorphisms (and linked polymorphisms) suggested to affect exposure to lamotrigine (UGT1A4*3 c.142T>G, rs2011425; UGT2B7–161C>T, rs7668258; ABCB1 1236C>T, rs1128503) to generate frequentist and Bayesian estimates of valproate effects (geometric means ratios [GMR]).

Results

The two studies yielded consistent results (replicated); hence, we analyzed combined data (total N = 471, 140 treated, 331 controls, 378 ABCG2 c.421C>A wt subjects, 93 variant carriers). Primary analysis: in variant carriers, valproate effect (GMR) on lamotrigine (treated, n = 21 vs. controls, n = 72) was around 60% higher than in wt subjects (treated, n = 119 vs. controls, n = 259)—ratio of GMRs 1.61 (95%CI 1.23–2.11) (frequentist) and 1.63 (95%CrI 1.26–2.10) (Bayes). Similar differences in valproate effects between variant carriers and wt subjects were found in the secondary analysis (valproate troughs up to 364 μmol/L vs. no valproate; or valproate ≥364 μmol/L vs. no valproate). Susceptibility of the estimates to unmeasured confounding was low.

Conclusion

Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine.

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乳腺癌症耐药性蛋白多态性ABCG2 c.421C>A（rs2231142）调节丙戊酸钠对成年癫痫患者拉莫三嗪谷浓度的影响。

背景：丙戊酸钠抑制拉莫三嗪的清除，并大大增加其浓度。我们评估了这种影响是否受到乳腺癌症耐药性蛋白多态性（ABCG2 c.421C>a）的调节。方法：在对成人癫痫患者进行的两项连续的独立研究中，拉莫三嗪单药治疗或与丙戊酸钠联合治疗：（i）暴露于丙戊酸钠被认为是治疗，（ii）稳定状态下的剂量调整拉莫三嗪谷是结果，（iii）ABCG2 c.421C>A基因型（野生型[wt]纯合性或变异携带）是测试的调节因子。我们使用熵平衡（主要分析）和精确/最优完全匹配（次要分析）来控制混杂，包括被认为影响拉莫三嗪暴露的多态性（和连锁多态性）（UGT1A4*3c.142T>G，rs2011425；UGT2B7-161C>T，rs7668258；ABCB1 1236C>T，rss1128503），以产生丙戊酸钠效应的频率学家和贝叶斯估计（几何平均数比值[GMR]）。结果：两项研究产生了一致的结果（重复）；因此，我们分析了组合数据（总N= 471140例接受治疗，331例对照，378例ABCG2 c.421C>A wt受试者，93例变异携带者）。初步分析：在变异携带者中，丙戊酸钠对拉莫三嗪的作用（治疗，n= 21与对照组，n= 72）比wt受试者（治疗后= 119与对照组，n= 259）-GMRs的比值为1.61（95%CI 1.23-2.11）（频率学家）和1.63（95%CI 1.26-2.10）（贝叶斯）。在二次分析中发现，变异携带者和wt受试者之间的丙戊酸钠作用存在类似差异（丙戊酸钠波谷高达364μmol/L与无丙戊酸钠相比；或丙戊酸钠≥364μmol/L vs.无丙戊酸盐）。估计值对未测量的混杂因素的敏感性较低。结论：rs2231142多态性调节丙戊酸钠对拉莫三嗪暴露的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.