Interactions of Enzyme-Inducing Antiepileptic Drugs with Direct-Acting Oral Anticoagulants: Risk of Thromboembolic Events

酶诱导抗癫痫药物与直接作用口服抗凝剂的相互作用：血栓栓塞事件的风险

基本信息

批准号：
10605482
负责人：
Emily Kate Acton
金额：
$ 4.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-03 至 2025-02-02
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605482
关键词：
Address Adult Affect Animal Experimentation Anticoagulants Anticoagulation Antiepileptic Agents Atrial Fibrillation Benchmarking Biological CYP3A4 gene Carrier Proteins Case Study Clinical Crossover Design Data Data Set Databases Disease Drug Interactions Drug Kinetics Drug Prescriptions Enzyme Induction Enzyme Interaction Enzymes Epilepsy Event Exposure to Failure Foundations Future Glycoproteins Goals Graph Hemorrhage High Prevalence Human In Vitro Incidence Individual Intestinal Absorption Investigation Kidney Knowledge Link Medical Mentors Metabolism Methodology Methods Nature Neuroepidemiology Observational Study Oral Outcome Patients Permeability Persons Pharmaceutical Preparations Pharmacoepidemiology Polypharmacy Population Postdoctoral Fellow Practice Guidelines Prevalence Proxy Pulmonary Embolism Reporting Research Research Personnel Risk Role Series Signal Transduction Therapeutic Thrombus Training absorption active comparator animal data career clinical risk cohort comparative safety comparison group complex data deep vein design experience experimental study health care service utilization high dimensionality high risk improved nervous system disorder novel screening skills therapeutic effectiveness thrombotic

项目摘要

Project Summary/Abstract Epilepsy affects over 70 million people worldwide, including an estimated 3.4 million in the US. Multiple widely- used antiepileptic drugs (AEDs) have off-target effects inducing key drug metabolizing enzymes, yielding numerous potential drug-drug interactions (DDIs). One such interaction with particularly high real-world relevance, but minimal clinical evidence, has been purported to occur between these enzyme-inducing AEDs (EI-AEDs) and direct-acting oral anticoagulants (DOACs). Co-prescription of AEDs with anticoagulants is common due to the frequent concurrency and causal links between epilepsy and the main indications for DOACs. EI-AEDs induce two crucial components of DOAC absorption and metabolism, which may lead to lower, potentially sub-therapeutic, levels of DOACs, and an increased risk of thromboembolic events. Evidence for these DDIs is composed primarily of in vitro and animal data. Existing human studies have limited real-world applicability due to both: substantial inconsistencies in findings, and methods that put the research at high risk for bias and confounding. Further, these human studies’ narrow focus on pairwise EI-AED/DOAC interactions disregards the potential role of higher-order drug-drug-drug interactions (3DIs), particularly given the high prevalence of polypharmacy in epilepsy populations. The goal of this research plan is to apply methodologically rigorous designs and leverage large-scale administrative claims data to address knowledge gaps regarding real- world DOAC therapeutic failures associated with EI-AED and concomitant drug interactions. In Aim 1, we will use a retrospective incident user cohort design to compare thromboembolic event rates in adults with epilepsy exposed to DOACs with EI-AEDs versus an active comparator group exposed to DOACs with non-enzyme inducing AEDs (NEI-AEDs). Given critical differences in utilization and thrombotic risk, we will separately analyze DOAC use for atrial fibrillation (1A) and deep vein thrombus/pulmonary embolism (1B). To generate effect estimates with vigorous control for observed and unobserved confounders (via proxy-adjustment), data-adaptive high-dimensional propensity scoring will be employed. In Aim 2, we will use a case-crossover design to explore the role of 3DIs in thromboembolic events in adults with epilepsy prescribed EI-AEDs and DOACs. A novel within- person approach to 3DI screening will be undertaken based on the temporal associations of concomitant drugs with thromboembolic events. Estimates will be quantitatively compared to a negative case group prescribed NEI- AEDs with DOACs in order to mitigate the direct effects and confounding by concomitant drugs, as well as to differentiate 3DI from DDI signals. Overall, this research will contribute to the advancement of prescribing standards for epilepsy patients requiring anticoagulation and provide benchmarks for future 3DI investigations. The valuable skills and experiences gained from this mentor-guided research and training will serve as essential foundations for the applicant to build continued postdoctoral research initiatives, and to advance towards a career as an independent investigator-clinician specializing in neuroepidemiology and pharmacoepidemiology.

项目概要/摘要癫痫症影响着全世界超过 7000 万人，其中美国估计有 340 万人。使用过的抗癫痫药物（AED）具有诱导关键药物代谢酶的脱靶效应，产生大量潜在的药物间相互作用（DDI）是一种与现实世界中特别高的相互作用。据称这些酶诱导 AED 之间存在相关性，但临床证据极少 (EI-AED) 和直接作用口服抗凝剂 (DOAC) AED 与抗凝剂的联合处方是。由于癫痫与 DOAC 主要适应症之间的频繁并发和因果关系，这种情况很常见。 EI-AED 诱导 DOAC 吸收和代谢的两个关键组成部分，这可能会导致较低的、潜在的亚治疗、DOAC 水平以及血栓栓塞事件风险增加的证据。这些 DDI 主要由体外和动物数据组成，现有的人类研究有限。由于以下两个原因导致的适用性：结果存在严重不一致，以及使研究面临高风险的方法此外，这些人类研究狭隘地关注成对的 EI-AED/DOAC 相互作用。忽略了高阶药物-药物-药物相互作用（3DI）的潜在作用，特别是考虑到高阶药物-药物-药物相互作用（3DI）本研究计划的目标是在方法论上进行应用。严格的设计并利用大规模行政索赔数据来解决有关实际情况的知识差距在目标 1 中，我们将与 EI-AED 和伴随的药物相互作用相关的世界 DOAC 治疗失败。使用回顾性用户队列设计来比较成人癫痫患者的血栓栓塞事件发生率暴露于带有 EI-AED 的 DOAC 与暴露于带有非酶的 DOAC 的活性比较组鉴于利用率和血栓形成风险的显着差异，我们将单独分析。 DOAC 用于治疗心房颤动 (1A) 和深静脉血栓/肺栓塞 (1B) 产生效果。对观察到的和未观察到的混杂因素进行严格控制的估计（通过代理调整），数据自适应在目标 2 中，我们将采用案例交叉设计来探索。 3DI 在成人癫痫患者血栓栓塞事件中的作用，处方 EI-AED 和 DOAC。 3DI 筛查的个体方法将根据伴随药物的时间关联进行血栓栓塞事件的估计值将与规定 NEI 的阴性病例组进行定量比较。 AED 与 DOAC 一起使用，以减轻并用药物的直接影响和混淆，以及总体而言，这项研究将有助于处方的进步。需要抗凝治疗的癫痫患者的标准，并为未来 3DI 研究提供基准。从导师指导的研究和培训中获得的宝贵技能和经验将至关重要为申请人建立持续的博士后研究计划和职业发展奠定基础作为一名独立研究者兼临床医生，专门研究神经流行病学和药物流行病学。