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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 1/2014

Open Access 01-01-2014 | Review Article

Clinical Pharmacokinetic and Pharmacodynamic Profile of Rivaroxaban

Authors: Wolfgang Mueck, Jan Stampfuss, Dagmar Kubitza, Michael Becka

Published in: Clinical Pharmacokinetics | Issue 1/2014

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Abstract

Rivaroxaban is an oral, direct Factor Xa inhibitor that targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It is absorbed rapidly, with maximum plasma concentrations being reached 2–4 h after tablet intake. Oral bioavailability is high (80–100 %) for the 10 mg tablet irrespective of food intake and for the 15 mg and 20 mg tablets when taken with food. Variability in the pharmacokinetic parameters is moderate (coefficient of variation 30–40 %). The pharmacokinetic profile of rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied. Elimination of rivaroxaban from plasma occurs with a terminal half-life of 5–9 h in healthy young subjects and 11–13 h in elderly subjects. Rivaroxaban produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for inhibition of Factor Xa activity can be described by an E max model, and prothrombin time prolongation by a linear model. Rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and, because rivaroxaban has multiple elimination pathways, it has no clinically relevant interactions with most commonly prescribed medications. Rivaroxaban has been approved for clinical use in several thromboembolic disorders.
Literature
1.
Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e44S–88S.PubMedCrossRef
2.
3.
4.
5.
Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765–75.PubMedCrossRef
6.
Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372:31–9.PubMedCrossRef
7.
Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776–86.PubMedCrossRef
8.
Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373:1673–80.PubMedCrossRef
9.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.PubMedCrossRef
10.
The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.CrossRef
11.
The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97.CrossRef
12.
Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9–19.PubMedCrossRef
13.
Perzborn E, Roehrig S, Straub A, et al. The discovery and development of rivaroxaban, an oral, direct Factor Xa inhibitor. Nat Rev Drug Discov. 2011;10:61–75.PubMedCrossRef
14.
Mueck W, Borris LC, Dahl OE, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost. 2008;100:453–61.PubMed
15.
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;50:675–86.PubMedCrossRef
16.
Mueck W, Becka M, Kubitza D, et al. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct Factor Xa inhibitor—in healthy subjects. Int J Clin Pharmacol Ther. 2007;45:335–44.PubMedCrossRef
17.
Roehrig S, Straub A, Pohlmann J, et al. Discovery of the novel antithrombotic agent 5-chloro-N-([(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct Factor Xa inhibitor. J Med Chem. 2005;48:5900–8.PubMedCrossRef
18.
19.
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;3:514–21.PubMedCrossRef
20.
Depasse F, Busson J, Mnich J, et al. Effect of BAY 59-7939—a novel, oral, direct Factor Xa inhibitor—on clot-bound Factor Xa activity in vitro [abstract no. P1104]. J Thromb Haemost. 2005;3(Suppl 1).
21.
Graff J, von Hentig N, Misselwitz F, et al. Effects of the oral, direct Factor Xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol. 2007;47:1398–407.PubMedCrossRef
22.
Samama MM. The mechanism of action of rivaroxaban—an oral, direct Factor Xa inhibitor—compared with other anticoagulants. Thromb Res. 2011;127:497–504.PubMedCrossRef
23.
Gerotziafas GT, Elalamy I, Depasse F, et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct Factor Xa inhibitor rivaroxaban. J Thromb Haemost. 2007;5:886–8.PubMedCrossRef
24.
Varin R, Mirshahi S, Mirshahi P, et al. Effect of rivaroxaban, an oral direct Factor Xa inhibitor, on whole blood clot permeation and thrombolysis: critical role of red blood cells [abstract no. 1064]. Blood (ASH Annual Meeting Abstracts). 2009;114.
25.
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;78:412–21.PubMedCrossRef
26.
Biemond BJ, Perzborn E, Friederich PW, et al. Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor. Thromb Haemost. 2007;97:471–7.PubMed
27.
Burghaus R, Coboeken K, Gaub T, et al. Evaluation of the efficacy and safety of rivaroxaban using a computer model for blood coagulation. PLoS ONE. 2011;6:e17626.PubMedCentralPubMedCrossRef
28.
Kubitza D, Mueck W, Becka M. Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation. Drug Saf. 2008;31:67–77.PubMedCrossRef
29.
30.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–9.PubMedCrossRef
31.
Levi M, Moore T, Castillejos C, et al. Effects of three-factor and four-factor prothrombin complex concentrates on the pharmacodynamics of rivaroxaban. J Thromb Haemost. 2013;11:167:Abstract OC 36.5.
32.
Rohde G. Determination of rivaroxaban—a novel, oral, direct Factor Xa inhibitor—in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;872:43–50.PubMedCrossRef
33.
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;61:873–80.PubMedCrossRef
34.
Stampfuss J, Kubitza D, Becka M, et al. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther. 2013;51:549–61.PubMedCrossRef
35.
Weinz C, Buetehorn U, Daehler HP, et al. Pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—in rats and dogs. Xenobiotica. 2005;35:891–910.PubMedCrossRef
36.
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;37:1056–64.PubMedCrossRef
37.
Gnoth MJ, Buetehorn U, Muenster U, et al. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther. 2011;338:372–80.PubMedCrossRef
38.
Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76:455–66.PubMedCrossRef
39.
40.
41.
Kubitza D, Becka M, Roth A, et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008;24:2757–65.PubMedCrossRef
42.
Kubitza D, Becka M, Roth A, et al. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct Factor Xa inhibitor. J Clin Pharmacol. 2013;53:249–55.PubMedCrossRef
43.
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;47:218–26.PubMedCrossRef
44.
Tanigawa T, Kaneko M, Hashizume K, et al. Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation. Drug Metab Pharmacokinet. 2013;28:59–70.PubMedCrossRef
45.
Jiang J, Hu Y, Zhang J, et al. Safety, pharmacokinetics and pharmacodynamics of single doses of rivaroxaban—an oral, direct Factor Xa inhibitor—in elderly Chinese subjects. Thromb Haemost. 2010;103:234–41.PubMedCrossRef
46.
Zhao X, Sun P, Zhou Y, et al. Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects. Br J Clin Pharmacol. 2009;68:77–88.PubMedCrossRef
47.
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;70:703–12.PubMedCrossRef
48.
49.
50.
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;76:89–98.PubMedCrossRef
51.
Mueck W, Eriksson BI, Bauer KA, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct Factor Xa inhibitor—in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47:203–16.PubMedCrossRef
52.
Clark B. Biology of renal aging in humans. Adv Ren Replace Ther. 2000;7:11–21.PubMed
53.
Fox KAA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32:2387–94.PubMedCrossRef
54.
Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374:29–38.PubMedCrossRef
55.
Xu XS, Moore K, Burton P, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. Br J Clin Pharmacol. 2012;74:86–97.PubMedCrossRef
56.
Gheorghiade M, Thyssen A, Zolynas R, et al. Pharmacokinetics and pharmacodynamics of rivaroxaban and its effect on biomarkers of hypercoagulability in patients with chronic heart failure. J Heart Lung Transplant. 2011;30:218–26.PubMedCrossRef
57.
Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513–23.PubMedCrossRef
58.
Barrett YC, Wang Z, Frost C, et al. Clinical laboratory measurement of direct Factor Xa inhibitors: Anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost. 2010;104:1263–71.PubMedCrossRef
59.
Samama MM, Martinoli JL, Le Flem L, et al. Assessment of laboratory assays to measure rivaroxaban—an oral, direct Factor Xa inhibitor. Thromb Haemost. 2010;103:815–25.PubMedCrossRef
60.
Lindhoff-Last E, Samama MM, Ortel TL, et al. Assays for measuring rivaroxaban: their suitability and limitations. Ther Drug Monit. 2010;32:673–9.PubMedCrossRef
61.
Mani H, Rohde G, Stratmann G, et al. Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. Thromb Haemost. 2012;108:191–8.PubMedCrossRef
62.
Samama MM, Contant G, Spiro TE, et al. Evaluation of the anti-Factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost. 2012;107:379–87.PubMedCrossRef
63.
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;46:549–58.PubMedCrossRef
64.
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;58:581–8.PubMedCrossRef
65.
Kubitza D, Becka M, Mueck W, et al. Rivaroxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor—has no clinically relevant interaction with naproxen. Br J Clin Pharmacol. 2007;63:469–76.PubMedCrossRef
66.
Kubitza D, Becka M, Mueck W, et al. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban—an oral, direct Factor Xa inhibitor—are not affected by aspirin. J Clin Pharmacol. 2006;46:981–90.PubMedCrossRef
67.
Kubitza D, Becka M, Mueck W, et al. Effect of co-administration of rivaroxaban and clopidogrel on bleeding time, pharmacodynamics and pharmacokinetics: a phase I study. Pharmaceuticals. 2012;5:279–96.PubMedCrossRef
68.
Kubitza D, Becka M, Schwers S, et al. Investigation of pharmacodynamic and pharmacokinetic interactions between rivaroxaban and enoxaparin in healthy male subjects. Clinical Pharm Drug Dev. 2013;2:270–7.CrossRef
69.
Kubitza D, Becka M, Mück W, et al. Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban in healthy subjects: a multicentre, randomized, placebo-controlled study. J Thromb Haemost. 2013;11:820 (Abstract PB 3.46-1).
70.
Kubitza D, Becka M, Roth A, et al. Absence of clinically relevant interactions between rivaroxaban—an oral, direct Factor Xa inhibitor—and digoxin or atorvastatin in healthy subjects. J Int Med Res. 2012;40:1688–707.PubMedCrossRef
71.
72.
Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36:386–99.PubMedCrossRef
73.
74.
Härtter S, Koenen-Bergmann M, Sharma A, et al. Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin. Br J Clin Pharmacol. 2012;74:490–500.PubMedCrossRef
75.
Zhang D, Frost CE, He K, et al. Investigating the enteroenteric recirculation of apixaban, a Factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. Drug Metab Dispos. 2013;41:906–15.PubMedCrossRef
76.
Samama MM. Which test to measure the anticoagulant effect of rivaroxaban: the anti-Factor Xa assay. J Thromb Haemost. 2013;11:579–80.PubMedCrossRef
77.
Lindhoff-Last E, Ansell J, Spiro T, et al. Laboratory testing of rivaroxaban in routine clinical practice: when, how, and which assays. Ann Med. 2013;45:423–9.PubMedCrossRef
78.
Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012;23:138–43.PubMedCrossRef
Metadata
Title
Clinical Pharmacokinetic and Pharmacodynamic Profile of Rivaroxaban
Authors
Wolfgang Mueck
Jan Stampfuss
Dagmar Kubitza
Michael Becka
Publication date
01-01-2014
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 1/2014
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-013-0100-7

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