The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations.

IF 7.4 2区医学 Q1 CLINICAL NEUROLOGY

CNS drugs Pub Date : 2024-05-01 Epub Date: 2024-03-23 DOI:10.1007/s40263-024-01077-0

Rachel Goldstein, Natalie Rabkin, Noa Buchman, Aviya R Jacobs, Khaled Sandouka, Bruria Raccah, Tamar Fisher Negev, Ilan Matok, Meir Bialer, Mordechai Muszkat

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引用次数: 0

Abstract

Background and objective: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM.

Methods: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (C_max) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC C_max of patients taking LEV were compared with the other two groups.

Results: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC C_max below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC C_max below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban C_max between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban C_max in a multivariate linear regression.

Conclusions: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban C_max and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban C_max. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

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与酶诱导型抗癫痫药物相比，左乙拉西坦对阿哌沙班和利伐沙班血浆峰浓度的影响

背景和目的：中风后癫痫是一项重要的临床挑战，因为它通常需要同时使用直接口服抗凝剂（DOACs）和抗癫痫药物（ASMs）进行治疗。左乙拉西坦（LEV）是一种已知不会诱导代谢酶的 ASM，有人建议它在接受 DOACs 治疗的患者中作为酶诱导 (EI) ASMs 的更安全替代品；然而，由于可能存在 P 糖蛋白诱导和竞争（基于临床前研究），目前的临床指南建议左乙拉西坦与 DOACs 合用时要谨慎。我们研究了 LEV 是否会影响阿哌沙班和利伐沙班的浓度，并与两个对照组进行了比较：(a) 接受 EI-ASMs 治疗的患者；(b) 未接受任何 ASM 治疗的患者：在这项回顾性观察研究中，我们监测了接受 LEV（n = 28）和 EI-ASM （n = 33）治疗的 203 名患者以及未接受任何 ASM 治疗的患者（n = 142）的阿哌沙班和利伐沙班峰值血浆浓度（Cmax）。酶诱导 ASM 包括卡马西平、苯妥英、苯巴比妥、普立米通和奥卡西平。我们收集了临床和实验室数据进行分析，并将服用 LEV 患者的 DOAC Cmax 与其他两组患者进行了比较：在203名患者中，55%为女性，平均年龄为78±0.8岁。186名患者服用阿哌沙班，17名患者服用利伐沙班。LEV 组 DOAC Cmax 低于治疗范围的患者比例为 7.1%，非 ASM 组为 10.6%，EI-ASM 组为 36.4%（p < 0.001）。服用 LEV 的患者 DOAC Cmax 低于治疗范围的几率（与对照组相比）没有显著差异（调整后的几率比 0.70，95% 置信区间 0.19-2.67，p = 0.61），但服用 EI-ASM 的患者的几率比对照组高 12.7 倍（p < 0.001）。在对接受阿哌沙班治疗的患者进行的分析中，接受LEV治疗的患者与非ASM对照组的阿哌沙班Cmax没有差异，在多变量线性回归中，LEV的临床使用与阿哌沙班Cmax的变化无关：在这项研究中，我们发现与 EI-ASMs 不同，LEV 的临床应用与阿哌沙班 Cmax 的降低无明显关联，与未接受任何 ASM 治疗的患者相似。我们的研究结果表明，LEV 与阿哌沙班和利伐沙班联用可能与阿哌沙班和利伐沙班 Cmax 降低无关。因此，需要进行前瞻性对照研究，以探讨 LEV-apixaban 或 LEV-rivaroxaban 联合用药对患者预后影响的可能非药代动力学机制。

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

CNS drugs 医学-精神病学

CiteScore

12.00

自引率

3.30%

发文量

审稿时长

6-12 weeks

期刊介绍： CNS Drugs promotes rational pharmacotherapy within the disciplines of clinical psychiatry and neurology. The Journal includes: - Overviews of contentious or emerging issues. - Comprehensive narrative reviews that provide an authoritative source of information on pharmacological approaches to managing neurological and psychiatric illnesses. - Systematic reviews that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement. - Adis Drug Reviews of the properties and place in therapy of both newer and established drugs in neurology and psychiatry. - Original research articles reporting the results of well-designed studies with a strong link to clinical practice, such as clinical pharmacodynamic and pharmacokinetic studies, clinical trials, meta-analyses, outcomes research, and pharmacoeconomic and pharmacoepidemiological studies. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in CNS Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.