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Thromb Haemost 2010; 103(01): 234-241
DOI: 10.1160/TH09-03-0196
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Safety, pharmacokinetics and pharmacodynamics of single doses of rivaroxaban – an oral, direct factor Xa inhibitor – in elderly Chinese subjects

Ji Jiang
1   The Clinical Pharmacology Research Center, Peking Union Medical College Hospital, P.R. China
,
Yufang Hu
1   The Clinical Pharmacology Research Center, Peking Union Medical College Hospital, P.R. China
,
Jianyan Zhang
1   The Clinical Pharmacology Research Center, Peking Union Medical College Hospital, P.R. China
,
Jueling Yang
1   The Clinical Pharmacology Research Center, Peking Union Medical College Hospital, P.R. China
,
Wolfgang Mueck
2   Clinical Pharmacology, Bayer Schering Pharma AG, Wuppertal, Germany
,
Dagmar Kubitza
2   Clinical Pharmacology, Bayer Schering Pharma AG, Wuppertal, Germany
,
Richard J. Bauer
3   Medical Affairs Asia-Pacific, Bayer Schering Pharma AG, Wuppertal, Germany
,
Ling Meng
4   Medical Department, Bayer HealthCare Company Ltd, Beijing, P.R. China
,
Pei Hu
1   The Clinical Pharmacology Research Center, Peking Union Medical College Hospital, P.R. China
› Author Affiliations
Further Information

Publication History

Received: 25 May 2009

Accepted after minor revision: 25 October 2009

Publication Date:
22 November 2017 (online)

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Summary

Rivaroxaban is a novel, oral, direct factor Xa (FXa) inhibitor for the prevention and treatment of thromboembolic disorders. The aim of this study was to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in healthy, elderly Chinese subjects. In this single-centre, single-blind, placebo-controlled, parallel-group, dose-escalation study, 79 subjects, aged 59–74 years (mean 62.8), were randomised to receive once-daily oral doses of rivaroxaban 5, 10, 20, 30 or 40 mg. Rivaroxaban was well tolerated: there was a low incidence of treatment-emergent adverse events and all events were of mild intensity. Rivaroxaban was absorbed rapidly, reaching maximum plasma concentrations within 2–4 hours. The PK of rivaroxaban were dose dependent over the dose range tested. Maximal inhibition of FXa occurred 2–3 hours after dosing and returned to baseline after 24–48 hours, reflecting rivaroxaban plasma concentrations. Inhibition of FXa was associated with dose-dependent effects on global clotting tests. There were no clinically relevant differences in rivaroxaban plasma concentrations between male and female subjects. In conclusion, rivaroxaban was well tolerated and was found to have predictable PK and PD in healthy, elderly Chinese subjects.

Keywords

Chinese subjects - factor Xa inhibitor - oral anticoagulant - rivaroxaban
 

  • References

  • 1 Fareed J, Hoppensteadt DA, Bick RL. An update on heparins at the beginning of the new millennium. Semin Thromb Hemost 2000; 26 (Suppl. 01) 5-21.
    PubMedGoogle Scholar
  • 2 Hirsh J, Anand SS, Halperin JL. et al. AHA Scientific Statement: guide to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association. Arterioscler Thromb Vasc Biol 2001; 21: E9.
    CrossrefPubMedGoogle Scholar
  • 3 Rosamond W, Flegal K, Friday G. et al. Heart disease and stroke statistics ﺹ 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115: e69-e171.
    CrossrefPubMedGoogle Scholar
  • 4 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107: I4-I8.
    PubMedGoogle Scholar
  • 5 Gross PL, Weitz JI. New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol 2008; 28: 380-386.
    CrossrefPubMedGoogle Scholar
  • 6 Geerts WH, Bergqvist D, Pineo GF. et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 381S-453S.
    CrossrefPubMedGoogle Scholar
  • 7 Albers GW, Amarenco P, Easton JD. et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 630S-669S.
    CrossrefPubMedGoogle Scholar
  • 8 Harrington RA, Becker RC, Cannon CP. et al. Antithrombotic therapy for nonST-segment elevation acute coronary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 670S-707S.
    CrossrefPubMedGoogle Scholar
  • 9 Singer DE, Albers GW, Dalen JE. et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 429S-456S.
    CrossrefPubMedGoogle Scholar
  • 10 World Health Organisation.. The world is fast ageing – have we noticed?. Available at: http://www.who.int/ageing/en.
    PubMedGoogle Scholar
  • 11 Miyasaka Y, Barnes ME, Gersh BJ. et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114: 119-125.
    CrossrefPubMedGoogle Scholar
  • 12 Ansell J, Bergqvist D. Current options in the prevention of thromboembolic disease. Drugs 2004; 64 (Suppl. 01) 1-5.
    PubMedGoogle Scholar
  • 13 Hylek EM. Oral anticoagulants. Pharmacologic issues for use in the elderly. Clin Geriatr Med 2001; 17: 1-13.
    CrossrefPubMedGoogle Scholar
  • 14 Spyropoulos AC. Managing oral anticoagulation requires expert experience and clinical evidence. J Thromb Thrombolysis 2006; 21: 91-94.
    CrossrefPubMedGoogle Scholar
  • 15 Ansell J, Hirsh J, Hylek E. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008; 133: 160S-198S.
    CrossrefPubMedGoogle Scholar
  • 16 Ansell J, Hirsh J, Dalen J. et al. Managing oral anticoagulant therapy. Chest 2001; 119: 22S-38S.
    CrossrefPubMedGoogle Scholar
  • 17 Hirsh J, Dalen J, Anderson DR. et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119: 8S-21S.
    CrossrefPubMedGoogle Scholar
  • 18 Hirsh J. Current anticoagulant therapy-unmet clinical needs. Thromb Res 2003; 109 (Suppl. 01) S1-S8.
    CrossrefPubMedGoogle Scholar
  • 19 Wells PS, Holbrook AM, Crowther NR. et al. Interactions of warfarin with drugs and food. Ann Intern Med 1994; 121: 676-683.
    CrossrefPubMedGoogle Scholar
  • 20 Levine MN, Raskob G, Beyth RJ. et al. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 287S-310S.
    CrossrefPubMedGoogle Scholar
  • 21 Agnelli G. Current issues in anticoagulation. Pathophysiol Haemost Thromb 2005; 34 (Suppl. 01) 2-9.
    CrossrefPubMedGoogle Scholar
  • 22 Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 2003; 23: 17-25.
    CrossrefPubMedGoogle Scholar
  • 23 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 01: 1504-1514.
    CrossrefPubMedGoogle Scholar
  • 24 Kubitza D, Haas S. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opin Investig Drugs 2006; 15: 843-855.
    CrossrefPubMedGoogle Scholar
  • 25 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 ﺹ an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 03: 514-521.
    CrossrefPubMedGoogle Scholar
  • 26 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: 5900-5908.
    CrossrefPubMedGoogle Scholar
  • 27 Piccini JP, Patel MR, Mahaffey KW. et al. Rivaroxaban, an oral direct factor Xa inhibitor. Expert Opin Invest Drugs 2008; 17: 925-937.
    CrossrefPubMedGoogle Scholar
  • 28 Eriksson BI, Borris L, Dahl OE. et al. Oral, direct Factor Xa inhibition with BAY 59–7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 04: 121-128.
    PubMedGoogle Scholar
  • 29 Eriksson BI, Borris LC, Dahl OE. et al. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114: 2374-2381.
    CrossrefPubMedGoogle Scholar
  • 30 Eriksson BI, Borris LC, Dahl OE. et al. Dose-escalation study of rivaroxaban (BAY 59-7939) – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Res 2007; 120: 685-693.
    CrossrefPubMedGoogle Scholar
  • 31 Turpie AG, Fisher WD, Bauer KA. et al. BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 2005; 03: 2479-2486.
    CrossrefPubMedGoogle Scholar
  • 32 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: 180-187.
    CrossrefPubMedGoogle Scholar
  • 33 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: 2242-2247.
    CrossrefPubMedGoogle Scholar
  • 34 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: 31-39.
    CrossrefPubMedGoogle Scholar
  • 35 Eriksson BI, Borris LC, Friedman RJ. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
    CrossrefPubMedGoogle Scholar
  • 36 Lassen MR, Ageno W, Borris LC. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-2786.
    CrossrefPubMedGoogle Scholar
  • 37 Turpie AG, Lassen MR, Davidson BL. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673-1680.
    CrossrefPubMedGoogle Scholar
  • 38 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: 2757-2765.
    CrossrefPubMedGoogle Scholar
  • 39 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: 218-226.
    CrossrefPubMedGoogle Scholar
  • 40 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.
    CrossrefPubMedGoogle Scholar
  • 41 Kubitza D, Becka M, Mueck W. et al. The effect of extreme age, and gender, on the pharmacology and tolerability of rivaroxaban ﺹ an oral, direct Factor Xa inhibitor. Blood. 2006 108: Abstract 905.
    PubMedGoogle Scholar
  • 42 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: 412-421.
    CrossrefPubMedGoogle Scholar
  • 43 Kubitza D, Becka M, Wensing G. et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 ﺹ an oral, direct Factor Xa inhibitor ﺹ after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: 873-880.
    CrossrefPubMedGoogle Scholar
  • 44 Zhao X, Sun P, Zhou Y. et al. Safety, 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.
    CrossrefPubMedGoogle Scholar
  • 45 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: 1056-1064.
    CrossrefPubMedGoogle Scholar
  • 46 Xarelto® Summary of Product Characteristics. Available at: http://www.xarelto.com/html/downloads/Xarelto_Summary_of_Product_Character-istics_30Sept2008.pdf. Accessed July 3, 2009.
    PubMedGoogle Scholar