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Interactions Between Direct Oral Anticoagulants (DOACs) and Antiseizure Medications: Potential Implications on DOAC Treatment

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Abstract

The use of direct oral anticoagulants (DOACs) is increasing because of their superior efficacy and safety compared with vitamin K antagonists. Pharmacokinetic drug interactions, particularly those involving cytochrome P450- mediated metabolism and P-glycoprotein transport, significantly affect the efficacy and safety of DOACs. In this article, we assess the effects of cytochrome P450- and P-glycoprotein-inducing antiseizure medications on DOAC pharmacokinetics in comparison to rifampicin. Rifampicin decreases to a varying extent the plasma exposure (area under the concentration–time curve) and peak concentration of each DOAC, consistent with its specific absorption and elimination pathways. For apixaban and rivaroxaban, rifampicin had a greater effect on the area under the concentration–time curve than on peak concentration. Therefore, using peak concentration to monitor DOAC concentrations may underestimate the effect of rifampicin on DOAC exposure. Antiseizure medications that are cytochrome P450 and P-glycoprotein inducers are commonly used with DOACs. Several studies have observed a correlation between the concomitant use of DOACs and enzyme-inducing antiseizure medications and DOAC treatment failure, for example, ischemic and thrombotic events. The European Society of Cardiology recommends avoiding this combination, as well as the combination of DOACs with levetiracetam and valproic acid, owing to a risk of low DOAC concentrations. However, levetiracetam and valproic acid are not cytochrome P450 or P-glycoprotein inducers, and the implications of their use with DOACs remain to be elucidated. Our comparative analysis suggests DOAC plasma concentration monitoring as a possible strategy to guide dosing owing to the predictable correlation between DOACs’ plasma concentration and effect. Patients taking concomitant enzyme-inducing antiseizure medications are at risk for low DOAC concentrations and subsequently, treatment failure and thus can benefit from DOAC concentration monitoring to prophylactically identify this risk.

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Acknowledgments

This work is abstracted from the Ph.D. thesis of Rachel Goldstein in partial fulfillment of the Ph.D. degree requirements for The Hebrew University of Jerusalem. Meir Bialer (meirb@ekmd.huji.ac.il) and Mordechai Muszkat  (muszkatm@hadassah.org.il) are co-corresponding authors for the paper.

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  1. Rachel Goldstein, Aviya R. Jacobs have equally contributed to this work.

Authors and Affiliations

  1. Department of Medicine, Faculty of Medicine, Hadassah Medical Center Mt. Scopus, Hebrew University of Jerusalem, Jerusalem, Israel

    Rachel Goldstein, Aviya R. Jacobs, Lana Zighan & Mordechai Muszkat

  2. Division of Clinical Pharmacy, Faculty of Medicine, Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel

    Rachel Goldstein

  3. Department of Pharmaceutics ,Faculty of Medicine, Ein Kerem, Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, 91120, Jerusalem, Israel

    Rachel Goldstein & Meir Bialer

  4. Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Clalit Health Services, Haifa, Israel

    Naomi Gronich

  5. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    Naomi Gronich

  6. David R. Bloom Center for Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel

    Meir Bialer

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This work was funded by a research grant from the Estates Committee, Israel Ministry of Justice (proposal submitted to the Chief Scientist, Ministry of Health) to Mordechai Muszkat 2021–2024.

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Meir Bialer received speaker’s or consultancy fees from Alkaloid, Boehringer Ingelheim, Clexio Bioscines, Guidepoint, Pharma Two B, Rekah-Vitamed, USWorldMeds, and Xenon Pharma. Rachel Goldstein, Aviya R. Jacobs, Lana Zighan, Naomi Gronich, and Mordechai Muszkat have no conflicts of interest that are directly relevant to the content of this article.

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RG, ARJ, LZ, NG, and MM produced an initial draft of the manuscript and conducted a literature search under guidance and supervision from MB and MM. RG, MB, and MB contributed to a critical evaluation of the data and to the revision and finalization of the manuscript. All authors have read and approved the final version of the manuscript, and agree to be accountable for the work.

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Goldstein, R., Jacobs, A.R., Zighan, L. et al. Interactions Between Direct Oral Anticoagulants (DOACs) and Antiseizure Medications: Potential Implications on DOAC Treatment. CNS Drugs 37, 203–214 (2023). https://doi.org/10.1007/s40263-023-00990-0

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