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Comparative Pharmacodynamics and Pharmacokinetics of Oral Direct Thrombin and Factor Xa Inhibitors in Development

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Abstract

For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents.

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Acknowledgements

This study was supported by a grant from Sahlgrenska University Hospital, Gothenburg, Sweden. Dr Eriksson has received fees as a consultant or speaker for Astellas, Bayer, Boehringer Ingelheim, Daiichi Sankyo and Takeda. Dr Quinlan has received fees as a consultant for Boehringer Ingelheim. Dr Weitz holds the Canada Research Chair in Thrombosis and the HSFO/J.F. Mustard Chair in Cardiovascular Research. Dr Weitz has received fees as a consultant or speaker for Bayer, Boehringer Ingelheim and BMS. The authors have no other conflicts of interest that are directly relevant to the content of this review.

Further information concerning ongoing trials of the compounds mentioned in the article is available online from www.clinicaltrials.gov.

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  1. University Hospital Sahlgrenska/Östra, Gothenburg, Sweden

    Bengt I. Eriksson

  2. Department of Radiology, Kings College Hospital, London, UK

    Daniel J. Quinlan

  3. Henderson Research Centre and McMaster University, Hamilton, Ontario, Canada

    Jeffrey I. Weitz

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  1. Bengt I. Eriksson
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Eriksson, B.I., Quinlan, D.J. & Weitz, J.I. Comparative Pharmacodynamics and Pharmacokinetics of Oral Direct Thrombin and Factor Xa Inhibitors in Development. Clin Pharmacokinet 48, 1–22 (2009). https://doi.org/10.2165/0003088-200948010-00001

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