功能缺失性ATP结合盒亚家族G成员2多态性ABCG2 c.421C>A降低癫痫成人患者的拉莫三嗪谷浓度。
The Loss-of-Function ATP Binding Cassette Subfamily G Member 2 Polymorphism ABCG2 c.421C>A Reduces Lamotrigine Trough Concentrations in Adults with Epilepsy.
作者信息
Božina Nada, Domjanović Iva Klarica, Sporiš Ivana Šušak, Ganoci Lana, Lovrić Mila, Trkulja Vladimir
机构信息
Department of Basic and Clinical Pharmacology, Zagreb University School of Medicine, Šalata 11, 10000, Zagreb, Croatia.
Croatian Agency for Medicinal Products and Medical Devices, Zagreb, Croatia.
出版信息
Eur J Drug Metab Pharmacokinet. 2025 Jan;50(1):17-22. doi: 10.1007/s13318-024-00925-0. Epub 2024 Nov 1.
BACKGROUND AND OBJECTIVES
The commonly used antiseizure medication lamotrigine is a substrate to ATP binding cassette subfamily G member 2 (ABCG2) transporter. The objective of this study was to evaluate the effect of the common loss-of-function polymorphism ABCG2 c.421C>A (rs2231142) on the lamotrigine trough concentrations at steady state in adults with epilepsy.
METHODS
In two consecutive studies (Study 1, Study 2) in patients on lamotrigine monotherapy, carriers of the variant ABCG2 c.421C>A allele (CA/AA) were considered exposed, and wild-type homozygotes (CC) were considered controls. They were mutually balanced on covariates (age, sex, body weight, several polymorphisms in genes encoding other transporter proteins and lamotrigine-metabolizing enzymes that have been suggested to affect exposure to lamotrigine) to estimate the exposure effect (geometric means ratios, GMRs) in each study separately and overall (individual patient data meta-analysis). The overall estimate was evaluated for sensitivity to residual confounding.
RESULTS
In both studies (exposed n = 28 vs. controls n = 103; exposed n = 44 vs. controls n = 153, in Study 1 and Study 2, respectively) and overall (exposed n = 72 vs. controls n = 256), dose-corrected lamotrigine trough concentrations were moderately lower in the exposed patients: frequentist GMR [95% CI] = 0.82 [0.63-1.08]; GMR = 0.69 [0.60-0.81] and GMR = 0.72 [0.63-0.83] in Study 1, Study 2 and overall, respectively; Bayes GMR [95% CrI] = 0.83 [0.68-1.00]; GMR = 0.69 [0.58-0.83] and GMR = 0.75 [0.65-0.86] in Study 1, Study 2 and overall, respectively. Estimates appeared resistant to unmeasured confounding-the E-values for the pooled point estimates were high, and estimates corrected for a strong hypothetical bias were GMR = 0.78 [0.68-0.90] frequentist and GMR = 0.81 [0.70-0.93] Bayes.
CONCLUSION
Polymorphism ABCG2 c.421C>A moderately reduces lamotrigine concentrations in adults with epilepsy.
背景与目的
常用的抗癫痫药物拉莫三嗪是ATP结合盒转运体G亚家族成员2（ABCG2）转运蛋白的底物。本研究的目的是评估常见的功能丧失性多态性ABCG2 c.421C>A（rs2231142）对癫痫成年患者稳态下拉莫三嗪谷浓度的影响。
方法
在两项连续的研究（研究1、研究2）中，对接受拉莫三嗪单药治疗的患者，将ABCG2 c.421C>A变异等位基因（CA/AA）携带者视为暴露组，野生型纯合子（CC）视为对照组。在协变量（年龄、性别、体重、编码其他转运蛋白和拉莫三嗪代谢酶的基因中的几种多态性，这些多态性被认为会影响拉莫三嗪的暴露）上对两组进行相互平衡，以分别估计每项研究及总体（个体患者数据荟萃分析）中的暴露效应（几何均数比，GMRs）。对总体估计值进行残余混杂敏感性评估。
结果
在两项研究中（研究1中暴露组n = 28，对照组n = 103；研究2中暴露组n = 44，对照组n = 153）以及总体（暴露组n = 72，对照组n = 256）中，暴露组患者经剂量校正的拉莫三嗪谷浓度均适度降低：研究1、研究2及总体的频率学派GMR[95%CI]分别为0.82[0.63 - 1.08]、0.69[0.60 - 0.81]和0.72[0.63 - 0.83]；研究1、研究2及总体的贝叶斯GMR[95%CrI]分别为0.83[0.68 - 1.00]、0.69[0.58 - 0.83]和0.75[0.65 - 0.86]。估计值似乎对未测量的混杂具有抗性——合并点估计值的E值较高，针对强假设偏倚校正后的估计值，频率学派GMR = 0.78[0.68 - 0.90]，贝叶斯GMR = 0.81[0.70 - 0.93]。
结论
ABCG2 c.421C>A多态性会适度降低癫痫成年患者体内的拉莫三嗪浓度。
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