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

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.

Cost-effectiveness of edoxaban for the treatment of venous thromboembolism based on the Hokusai-VTE study

“…[38][39][40] There is also wide variation in treatment duration, the proportion of unprovoked/provoked VTE cases, the number of PE patients and the disease extensiveness that were studied in the Phase 3 clinical trials. Furthermore, differences in the pharmacological and pharmacokinetic profiles [41] also led to differences in dosing frequency and food-drug interactions across the NOACs. Hence, depending on their clinical characteristics, patients may be better suited to one agent over another in clinical practice.…”

TEG ir naujieji peroraliniai antikoaguliantai

“…Rivaroksabanas yra geriamasis selektyvus tiesioginis aktyvuoto X (Xa) faktoriaus inhibitorius [5,14]. Rivaroksabanas gali slopinti laisvą, prisijungusį prie trombocitų ir protrombinazės komplekse esantį Xa faktorių, kai tuo tarpu netiesioginiai Xa faktoriaus inhibitoriai (pvz., fondaparinuksas) slopina tik protrombinazės komplekse esantį Xa faktorių [5,15,16]. Vaistas pasižymi greita veikimo pradžia, numatomomis bei dozei proporcingomis farmakokinetinėmis ir farmakodinaminėmis savybėmis.…”

“…Iš organizmo vaistas šalinamas dviem keliais: didžioji dalis (apie 66%) -per inkstus, likusi -su tulžimi. Asmenys, sergantys lėtiniu inkstų ar kepenų funkcijos nepakankamumu, rivaroksabaną turėtų vartoti atsargiai dėl padidėjusios kraujavimo rizikos [15][16][17][18].…”

Warfarin Versus New Agents: Interpreting the Data

“…This may not be as important a problem as some suggest, because rapid reversal of warfarin is not simple and requires infusions of fresh frozen plasma or factor concentrates, the latter of which have been shown to be able to reverse anticoagulation with several of the new agents. 35 Specific antidotes are also being developed for factor Xa inhibitors. 36 Finally, warfarin is available as a generic medication and is relatively inexpensive.…”