Association rate constants rationalise the pharmacodynamics of apixaban and rivaroxaban

Thrombosis and Haemostasis
Georges JourdiB Le Bonniec

Abstract

Rivaroxaban and apixaban are selective direct inhibitors of free and prothrombinase-bound factor Xa (FXa). Surprisingly prothrombin time (PT) is little sensitive to clinically relevant changes in drug concentration, especially with apixaban. To investigate this pharmacodynamic discrepancy we have compared the kinetics of FXa inhibition in strictly identical conditions (pH 7.48, 37 °C, 0.15 M). KI values of 0.74 ± 0.03 and 0.47 ± 0.02 nM and kon values of 7.3 ± 1.6 10(6) and 2.9 ± 0.6 10(7) M(-1) s(-1) were obtained for apixaban and rivaroxaban, respectively. To investigate if these constants rationalise the inhibitor pharmacodynamics, we used numerical integration to evaluate impact of FXa inhibition on thrombin generation assay (TGA) and PT. Simulation predicted that in TGA triggered with 20 pM tissue factor, 100 ng/ml apixaban or rivaroxaban increased 1.8- or 3.0-fold the lag time and 1.4- or 2.0-fold the time to peak, whilst decreasing 1.2- or 3.1-fold the maximum thrombin and 1.7- or 3.5-fold the endogenous thrombin potential. These numbers were consistent with those obtained through the corresponding TGA triggered in plasma spiked with apixaban or rivaroxaban. Simulated PT ratios were also consistent with the corresponding...Continue Reading

References

Jan 1, 1979·Methods in Enzymology·J W Williams, J F Morrison
Mar 15, 2002·The Journal of Biological Chemistry·Matthew F HockinKenneth G Mann
Jul 11, 2003·Pathophysiology of Haemostasis and Thrombosis·H Coenraad HemkerSuzette Béguin
Oct 30, 2003·The Journal of Biological Chemistry·Elsa P BianchiniBernard F Le Bonniec
Mar 8, 2005·Journal of Thrombosis and Haemostasis : JTH·E PerzbornA Straub
Feb 9, 2010·Arteriosclerosis, Thrombosis, and Vascular Biology·Elisabeth PerzbornVolker Laux
Sep 2, 2010·Thrombosis and Haemostasis·Meyer Michel SamamaFrançois Depasse
Oct 14, 2010·PLoS Computational Biology·Manash S ChatterjeeScott L Diamond
Oct 16, 2010·Journal of Thrombosis and Haemostasis : JTH·A HillarpT L Lindahl
Dec 22, 2010·Journal of Enzyme Inhibition and Medicinal Chemistry·Joseph M LuettgenAlan R Rendina
Feb 12, 2011·The New England Journal of Medicine·Stuart J ConnollyUNKNOWN AVERROES Steering Committee and Investigators
Aug 13, 2011·The New England Journal of Medicine·Manesh R PatelUNKNOWN ROCKET AF Investigators
Aug 30, 2011·The New England Journal of Medicine·Christopher B GrangerUNKNOWN ARISTOTLE Committees and Investigators
Oct 12, 2011·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Job HarenbergChristel Weiss
Dec 3, 2011·Journal of Cardiovascular Pharmacology and Therapeutics·Carlos AlvesAna Filipa Macedo
May 31, 2012·Journal of Thrombosis and Haemostasis : JTH·K G Mann
Nov 20, 2012·Thrombosis Research·H Coenraad Hemker, R Kremers
Jun 15, 2013·Thrombosis and Haemostasis·Jonathan DouxfilsFrançois Mullier
Jul 3, 2013·The New England Journal of Medicine·Giancarlo AgnelliUNKNOWN AMPLIFY Investigators
Aug 26, 2014·VASA. Zeitschrift für Gefässkrankheiten·Mirko Hirschl, Michael Kundi
Sep 3, 2014·Thrombosis Research·Dieter AdelmannEva Schaden

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Citations

Oct 17, 2015·Expert Review of Cardiovascular Therapy·Noel C ChanJohn W Eikelboom
Jan 27, 2017·Thrombosis and Haemostasis·Annemarie BluecherOliver C Singer
Feb 6, 2017·Journal of Clinical Pathology·Leyla CalmetteAnne Godier
Apr 30, 2016·Circulation Research·Scott L Diamond
Jan 4, 2019·International Journal of Laboratory Hematology·Romain SiriezJonathan Douxfils
Dec 7, 2018·Journal of Thrombosis and Thrombolysis·Syed MahamadMichelle Sholzberg
Oct 12, 2018·European Journal of Anaesthesiology·Claire PailleretCharles M Samama
Oct 6, 2017·International Journal of Laboratory Hematology·L SeyveR Marlu
Oct 3, 2018·Clinical and Applied Thrombosis/hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis·Elias KyriakouArgirios E Tsantes
May 16, 2019·Clinical and Applied Thrombosis/hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis·Fakiha SiddiquiJawed Fareed
Oct 11, 2020·International Journal of Laboratory Hematology·Jonathan EvrardJonathan Douxfils
Jul 21, 2020·Seminars in Thrombosis and Hemostasis·Mark SchreuderMettine H A Bos
Dec 29, 2020·International Journal of Laboratory Hematology·Geoffrey Foulon-PintoVirginie Siguret
Dec 15, 2020·Research and Practice in Thrombosis and Haemostasis·Genmin LuPamela B Conley
Dec 27, 2019·The Annals of Thoracic Surgery·Iqbal H JafferJeffrey I Weitz
Apr 9, 2018·Pesticide Biochemistry and Physiology·Georges JourdiVirginie Siguret
Jul 13, 2021·International Journal of Laboratory Hematology·Michael HardyFrançois Mullier

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