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Thromb Haemost 2015; 114(01): 78-86
DOI: 10.1160/TH14-10-0877
Coagulation and Fibrinolysis
Schattauer GmbH

Association rate constants rationalise the pharmacodynamics of apixaban and rivaroxaban

Georges Jourdi
1   INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
,
Virginie Siguret
1   INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
3   AP-HP, Hôpital Lariboisière, Paris, France
,
Anne Céline Martin
1   INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
4   Hôpital Val de Grâce, Paris, France
,
Jean-Louis Golmard
5   Université Pierre et Marie Curie, Paris, France
,
Anne Godier
1   INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
6   Fondation Rothschild, Paris, France
,
Charles-Marc Samama
1   INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
7   AP-HP, Hôpital Cochin, Paris, France
,
Pascale Gaussem
1   INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
8   AP-HP, Hôpital Européen Georges Pompidou, Paris, France
,
Isabelle Gouin-Thibault   *
1   INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
7   AP-HP, Hôpital Cochin, Paris, France
,
Bernard Le Bonniec   *
1   INSERM UMR_S1140, Faculté de Pharmacie, Paris, France
2   Université Paris Descartes, Sorbonne Paris Cité, Paris, France
› Author Affiliations Financial support: This study was supported by the CONNY-MAEVA charitable Foundation.
Further Information

Publication History

Received: 23 October 2014

Accepted after major revision: 17 January 2015

Publication Date:
22 November 2017 (online)

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Summary

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 ± 1.6 106 and 2.9 ± 0.6 107 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 plasma PT: markedly less sensitive to apixaban than to rivaroxaban. Analogous differences in TGA and PT were obtained irrespective of the drug amount added. We concluded that kon values for FXa of apixaban and rivaroxaban rationalise the unexpected lower sensitivity of PT and TGA to the former.

Keywords

Coagulation factors - protease inhibitors - computer simulation - blood coagulation tests - prothrombin time

* These authors share equal senior authorship.


 

  • References

  • 1 Ageno W, Gallus AS, Wittkowsky A. et al. Oral anticoagulant therapy: Anti-thrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: 44S-88S.
    CrossrefPubMedGoogle Scholar
  • 2 Alves C, Batel-Marques F, and Macedo AF. Apixaban and rivaroxaban safety after hip and knee arthroplasty: a meta-analysis. J. Cardiovasc Pharmacol Ther 2012; 17: 266-276.
    CrossrefPubMedGoogle Scholar
  • 3 Connolly SJ, Eikelboom J, Joyner C. et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
    CrossrefPubMedGoogle Scholar
  • 4 Granger CB, Alexander JH, McMurray JJV. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
    CrossrefPubMedGoogle Scholar
  • 5 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
    CrossrefPubMedGoogle Scholar
  • 6 Prins MH, Lensing AW, Bauersachs R. et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11: 21.
    CrossrefPubMedGoogle Scholar
  • 7 Agnelli G, Buller HR, Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799-808.
    CrossrefPubMedGoogle Scholar
  • 8 Baglin T, Hillarp A, Tripodi A. et al. Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: A recommendation from the subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2013; 11: 756-760.
    CrossrefPubMedGoogle Scholar
  • 9 Harenberg J, Marx S, Krämer R. et al. Determination of an international sensitivity index of thromboplastin reagents using a WHO thromboplastin as calibrator for plasma spiked with rivaroxaban. Blood Coagul Fibrinolysis 2011; 22: 637-641.
    CrossrefPubMedGoogle Scholar
  • 10 Dale BJ, Ginsberg JS, Johnston M. et al. Comparison of the effects of apixaban and rivaroxaban on prothrombin and activated partial thromboplastin times using various reagents. J Thromb Haemost 2014; 12: 1-6.
    PubMedGoogle Scholar
  • 11 Gouin-Thibault I, Flaujac C, Delavenne X. et al. Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicenter French GEHT study. Thromb Haemost 2014; 111: 240-248.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Douxfils J, Chatelain C, Chatelain B. et al. Impact of apixaban on routine and specific coagulation assays: a pratical laboratory guide. Thromb Haemost 2013; 110: 283-294.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Harenberg J, Du S, Weiss C. et al. Report of the Subcommittee on Control of Anticoagulation on the determination of the anticoagulant effects of apixaban: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12: 801-804.
    CrossrefPubMedGoogle Scholar
  • 14 Luettgen JM, Knabb RM, He K. et al. Apixaban inhibition of factor Xa: Microscopic rate constants and inhibiton mechanism in purified protein systems and in human plasma. J Enzyme Inhib Med Chem 2011; 26: 514-526.
    CrossrefPubMedGoogle Scholar
  • 15 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939 – an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 03: 514-521.
    CrossrefPubMedGoogle Scholar
  • 16 Perzborn E, Roehrig S, Straub A. et al. A new oral factor Xa inhibitor. Arterioscler. Thromb Vasc Biol 2010; 30: 376-381.
    CrossrefPubMedGoogle Scholar
  • 17 Pinto DJ, Orwat MJ, Koch S. et al. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo(3,4c)pyridine3carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 2007; 50: 5339-5356.
    CrossrefPubMedGoogle Scholar
  • 18 Le Bonniec BF, Betz A, Guinto ER. et al. Mapping of the thrombin des-ETW conformation by using site-directed mutants of hirudin. Evidence for the induction of nonlocal modifications by mutagenesis. Biochemistry 1994; 33: 3959-3966.
    CrossrefPubMedGoogle Scholar
  • 19 Cha S, Agarwal RP, Parks RE. Tight-binding inhibitors-II. Non-steady state nature of inhibition of milk xanthine oxidase by allopurinol and alloxanthine and of human erythrocytic adenosine deaminase by coformycin. Biochem Pharmacol 1975; 24: 2187-2197.
    CrossrefPubMedGoogle Scholar
  • 20 Williams JW, Morrison JF. The kinetics of reversible tight-binding inhibition. Methods Enzymol 1979; 63: 437-467.
    PubMedGoogle Scholar
  • 21 Bianchini EP, Pike RN, Le Bonniec BF. The elusive role of the potential factor X cation-binding exosite-1 in substrate and inhibitor interactions. J Biol Chem 2004; 279: 3671-3679.
    CrossrefPubMedGoogle Scholar
  • 22 Hemker HC, Giesen P, Al Dieri. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
    CrossrefPubMedGoogle Scholar
  • 23 Hemker HC, Kremers R. Data management in thrombin generation. Thromb Res 2013; 131: 3-11.
    CrossrefPubMedGoogle Scholar
  • 24 Camici GG, Steffel J, Akhmedov A. et al. Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation 2006; 114: 1512-1521.
    CrossrefPubMedGoogle Scholar
  • 25 Jones KC, and Mann KG. A model for the tissue factor pathway to thrombin. II. A mathematical simulation. J Biol Chem 1994; 269: 23367-23373.
    PubMedGoogle Scholar
  • 26 Hockin MF, Jones KC, Everse SJ. et al. A model for the stoichiometric regulation of blood cogulation. J Biol Chem 2002; 277: 18322-18333.
    CrossrefPubMedGoogle Scholar
  • 27 Wong PC, White A, Luettgen J. Inhibitory effect of apixaban compared with rivaroxaban and dabigatran on thrombin generation assay. Hosp Pract 2013; 1995: 19-25.
    PubMedGoogle Scholar
  • 28 Mann KG. Is there value in kinetic modeling of thrombin generation? Yes. J Thromb Haemost 2012; 10: 1463-1469.
    CrossrefPubMedGoogle Scholar
  • 29 Chatterjee MS, Denney WS, Jing H. et al. Systems biology of coagulation initiation: kinetics of thrombin generation in resting and activated human blood. PLoS Comput Biol 2010; 9.
    PubMedGoogle Scholar
  • 30 Samama MM, Amiral J, Guinet C. et al. An optimised, rapid chromogenic assay, specific for measuring direct factor Xa inhibitors (rivaroxaban) in plasma. Thromb Haemost 2010; 104: 1078-1079.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Gong IY, and Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban and apixaban. J Cardiol 2013; 29: S24-S33.
    PubMedGoogle Scholar
  • 32 Eller T, Busse J, Dittrich M. et al. Dabigatran, rivaroxaban, apixaban, argatroban and fondaparinux and their effects on coagulation POC and platelet function tests. Clin Chem Lab Med CCLM FESCC 2014; 52: 835-844.
    PubMedGoogle Scholar
  • 33 Hillarp A, Baghaei F, Fagerberg Blixter I. et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Hae-most 2011; 09: 133-139.
    CrossrefPubMedGoogle Scholar
  • 34 Halperin JL, Hankey GJ, Wojdyla DM. et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with non valvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Fcator Xa Inhibition Compared With Vitamin K An taginism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation 2014; 130: 138-146.
    CrossrefPubMedGoogle Scholar
  • 35 Hankey GJ, Patel MR, Stevens SR. et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol 2012; 11: 315-322.
    CrossrefPubMedGoogle Scholar
  • 36 Hirschl M, Kundi M. New oral anticoagulants in the treatment of acute venous thromboembolism – a systematic review with indirect comparisons. VASA 2014; 43: 353-364.
    CrossrefPubMedGoogle Scholar
  • 37 Adelmann D, Wiegele M, Wohlgemuth RK. et al. Measuring the activity of apixaban and rivaroxaban with rotational thromboelastometry. Thromb Res 2014; 134: 918-923.
    CrossrefPubMedGoogle Scholar