This page contains a Flash digital edition of a book.
Introduction: Factor Xa


metabolites in faeces.18


Renal excretion


of apixaban accounts for approximately 27% of total clearance. Additional biliary and intestinal excretion has also been described.


Edoxaban is another highly specific, direct oral inhibitor of Factor Xa, with an approximate 10,000-fold selectivity for Factor Xa over thrombin.19


In a single-


dose study in healthy subjects, the maximum plasma concentration of 60mg edoxaban was observed at 1.5 hours after administration, corresponding to the maximum inhibition of Factor Xa activity, which returned to baseline levels by 12 hours. The half-life is 10–14 hours; plasma protein binding is 40–60%.20


Rivaroxaban reversibly binds to the catalytic pocket of Factor Xa, thereby inhibiting its coagulant activity.13,14


It


competitively inhibits Factor Xa and is 10,000-fold more selective for Factor Xa than other related serine proteases. Unlike indirect Factor Xa inhibitors, rivaroxaban inhibits both free- and clot-bound Factor Xa. The bioavailability of rivaroxaban is high (>80%) and the maximum concentration is observed two to four hours after oral intake.13


It is


extensively (>90%) bound to plasma proteins, and its maximum plasma concentration is dose dependent. The half-life ranges from five to nine hours and the kidneys excrete 66% of the orally ingested drug.15


Other modes of


excretion involve faecal elimination and hepatic metabolism.


Conclusions


Factor Xa is a crucial element of the coagulation cascade. With its unique position in the coagulation pathway and its critical role in the initiation of thrombin generation, Factor Xa has emerged as an attractive target for anticoagulation. The availability of the new generation of specific


anticoagulants, including the oral direct Factor Xa inhibitors, has resulted in a paradigm shift in anticoagulation, both for stroke prevention in atrial fibrillation as well as the treatment and long-term prevention of venous thromboembolism. l


References 1. Davie EW, Ratnoff SI. Waterfall sequence for intrinsic blood clotting. Science 1964;145:1310–12.


6


2. Steffel J, Lüscher TF, Tanner FC. Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation


www.hospitalpharmacyeurope.com


2006;7;113:722–31.


3. Holy EW, Tanner FC. Tissue factor in vascular diseases: pathophysiology and pharmacological implications. Adv Pharmacol 2010;59:259–92.


4. Holy EW, Beer JH. Update on the status of new oral anticoagulants for stroke prevention in atrial fibrillation: ringing in a new era. Cardiovasc Med 2013;16:103–14.


5. Steffel J, Braunwald E. Novel oral anticoagulants: focus on stroke prevention and treatment of venous thrombo-embolism. Eur Heart J 2011;32(16):1968–76.


6. Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008;141:757–63.


7. Hirsh J, Raschke R. Heparin and low-molecular- weight heparin: the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:188S–203S.


8. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688–99.


9. O’Reilly RA. Vitamin K and the oral anticoagulant drugs. Annu Rev Med 1976;27:245–61.


10. Breckenridge A. Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol 1978;15:19–26.


11. Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 2005;44:1227–46.


12. Bauer KA. Fondaparinux: a new synthetic and selective inhibitor of Factor Xa. Best Pract Res Clin Haematol 2004;17:89–104.


13. Perzborn E 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;3: 514–21.


14. Perzborn E et al. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol 2010;30:376–81.


15. Kubitza D et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–21.


16. He K et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet 2011;36:129–39. 17. Pinto DJP et al. Discovery of


1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin- 1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c] pyridine-3-carboxamide (apixaban, BMS- 562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 2007;50:5339–56.


18. Raghavan N et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009;37:74–81.


19. Furugohri T et al. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. Thromb Haemost 2008;6:1542–9.


20. Ogata K et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel Factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010;50:743–53.


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36