Rivaroxaban – pharmacological profile

Czech version

Authors: K. Urbánek
Authors‘ workplace: Ústav farmakologie, LF UP a FN Olomouc
Published in: Kardiol Rev Int Med 2017, 19(1): 39-44

Overview

Rivaroxaban is an oral selective, direct factor Xa inhibitor. It has well predictable pharmacodynamics and pharmacokinetics. Depending on the size of the dose, it inhibits thrombin formation after 24 hours. It does not block the existing thrombin activity and thus enables continued activation of endogenous anticoagulant factors. After oral administration it is well absorbed, its bioavailability varies between 80 and 100%. It is bound to plasma proteins in 92 to 95%, its average distribution volume is 50 litres. The main metabolising systems are cytochromes P450 3A4 and 2J2. It is excreted mainly via the kidneys; about one third of the administered amount being excreted unchanged, primarily by tubular secretion. The remaining two thirds are excreted as inactive metabolites in urine and bile. The median terminal half-life in younger individuals is 5–9 hours, and 11–13 hours in older individuals. Rivaroxaban pharmacokinetics is minimally affected by age or sex of the patient, and does not require dose adjustments in patients with extremely low or high or with mild-to-moderate renal or hepatic insufficiency.

Keywords:
rivaroxaban – anticoagulants – pharmacodynamics – pharmacokinetics

Sources

1. Piccini JP, Patel MR, Mahaffey KW et al. Rivaroxaban, an oral direct factor Xa inhibitor. Expert Opin Investig Drugs 2008; 17(6): 925– 937. doi: 10.1517/ 13543784.17.6.925.

2. Perzborn E, Roehrig S, Straub A et al. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol 2010; 30(3): 376– 381. doi: 10.1161/ ATVBAHA.110.202978.

3. Gulseth MP, Michaud J, Nutescu EA. Rivaroxaban: an oral direct inhibitor of factor Xa. Am J Health Syst Pharm 2008; 65(16): 1520– 1529. doi: 10.2146/ ajhp070624.

4. Kubitza D, Becka M, Voith B et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78(4): 412– 421. doi: 10.1016/ j.clpt.2005.06.011.

5. Kubitza D, Becka M, Wensing G et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 – an oral, direct Factor Xa inhibitor-after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61(12): 873– 880. doi: 10.1007/ s00228-005-0043-5.

6. Weinz C, Schwarz T, Kubitza D et al. Metabolism and excretion of rivaroxaban, an oral, direct Factor Xa inhibitor, in rats, dogs and humans. Drug Metab Dispos 2009; 37(5): 1056– 1064. doi: 10.1124/ dmd.108.025569.

7. Mueck W, Stampfuss J, Kubitza D et al. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014; 53(1): 1– 16. doi: 10.1007/ s40262-013-0100-7.

8. Kubitza D, Becka M, Zuehlsdorf M et al. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol 2007; 47(2): 218– 226. doi: 10.1177/ 0091270006296058.

9. Kubitza D, Becka M, Mueck W et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010; 70(5): 703– 712. doi: 10.1111/ j.1365-2125.2010.03753.x.

10. Kubitza D, Roth A, Becka M et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2013; 76(1): 89– 98. doi: 10.1111/ bcp.12054.

11. Agnelli G, Gallus A, Goldhaber SZ et al. Treatment of proximal deep-vein thrombosis with the oral direct Factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in patients with acute symptomatic deep-vein thrombosis) study. Circulation 2007; 116(2): 180– 187. doi: 10.1161/ circulationaha.106.668020.

12. Buller HR, Lensing AW, Prins MH et al. A dose--ranging study evaluating once-daily oral administration of the Factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the EINSTEIN-DVT dose--ranging study. Blood 2008; 112(6): 2242– 2247. doi: 10.1182/ blood-2008-05-160143.

13. Mueck W, Lensing AW, Agnelli G et al. Rivaroxaban population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50(10): 675– 686. doi: 10.2165/ 11595320-000000000-00000.

14. Coleman CI, Roberts MS, Sobieraj DM et al. Effect of dosing frequency on chronic cardiovascular disease medication adherence. Curr Med Res Opin 2012; 28: 1– 12. doi: 10.1185/ 03007995.2012.677419.

15. Piccini JP, Hellkamp AS, Washam JB et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation 2016; 133(4): 352– 360. doi: 10.1161/ CIRCULATIONAHA.115.018544.

16. SPC Xarelto®. Dostupné z: http:/ / www.sukl.cz/ modules/ medication/ detail.php?kod=0500717.

17. Kubitza D, Becka M, Zuehlsdorf M et al. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 2006; 46(5): 549– 558. doi: 10.1177/ 0091270006286904.

18. Moore KT, Plotnikov AN, Thyssen A et al. Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban. J Cardiovasc Pharmacol 2011; 58(6): 581– 588. doi: 10.1097/ FJC.0b013e31822f6c2b.

19. Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in heatlhy subjects. Br J Clin Pharmacol 2013; 79(3): 455– 466. doi: 10.1111/ bcp.12075.

20. Moore KT, Vaidyanathan S, Natarajan J et al. An open-label study to estimate the effect of steady-state erythromycin on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban in subjects with renal impairment and normal renal function. J Clin Pharmacol 2014; 54(12): 1407– 1420. doi: 10.1002/ jcph.352.

21. Wannhoff A, Weiss KH, Stremmel W et al. Increased levels of rivaroxaban in patients after liver transplantation treated with cyclosporine A. Transplantation 2014; 98(2): e12– e13. doi: 10.1097/ TP.0000000000000223.

22. Camm AJ, Amarenco P, Haas S et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation Eur Heart J 2016; 37(14): 1145– 1153. doi: 10.1093/ eurheartj/ ehv466.

23. Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. ROCKET AF Investigators. N Engl J Med 2011; 365(10): 883– 891. doi: 10.1056/ NEJMoa1009638.

24. Watkins PB, Desai M, Berkowitz SD et al. Evaluation of drug induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug Saf 2011; 34(3): 243– 252. doi: 10.2165/ 11586600-000000000-00000.

25. Lambert A, Cordeanu M, Gaertner S et al. Rivaroxaban-induced liver injury: Results from a venous thromboembolism registry. Int J Cardiol 2015; 191: 265– 266. doi: 10.1016/ j.ijcard.2015.04.2.