Thromb Haemost 2012; 107(02): 379-387
DOI: 10.1160/TH11-06-0391
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls

Meyer Michel Samama
1   Hótel-Dieu University Hospital, Paris, France
2   Biomnis Laboratories R&D, Ivry-sur-Seine, France
,
Genevieve Contant
3   Diagnostica Stago SA, Gennevilliers, France
,
Theodore E. Spiro
4   Bayer Healthcare Pharmaceuticals Inc., Montville, New Jersey, USA
,
Elisabeth Perzborn
5   Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany
,
Céline Guinet
2   Biomnis Laboratories R&D, Ivry-sur-Seine, France
,
Yves Gourmelin
3   Diagnostica Stago SA, Gennevilliers, France
,
Léna Le Flem
2   Biomnis Laboratories R&D, Ivry-sur-Seine, France
,
Gabriele Rohde
5   Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany
,
Jean Luc Martinoli
3   Diagnostica Stago SA, Gennevilliers, France
,
for the Rivaroxaban Anti-Factor Xa Chromogenic Assay Field Trial Laboratories › Institutsangaben
Financial support: This study was supported by Bayer HealthCare Pharmaceuticals and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Weitere Informationen

Publikationsverlauf

Received: 09. Juni 2011

Accepted after major revision: 30. Oktober 2011

Publikationsdatum:
29. November 2017 (online)

Summary

Rivaroxaban is an oral, direct factor Xa inhibitor. Routine coagulation monitoring is not required, but a quantitative determination of rivaroxaban concentrations might be useful in some clinical circumstances. This multicentre study assessed the suitability of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations (ng/ml) using rivaroxaban calibrators and controls, and the inter-laboratory precision of the measurement. Twenty-four centres in Europe and North America were provided with sets of rivaroxaban calibrators (0, 41, 209 and 422 ng/ml) and a set of rivaroxaban pooled human plasma controls (20, 199 and 662 ng/ml; the concentrations were unknown to the participating laboratories). The evaluation was carried out over 10 days by each laboratory using local anti-factor Xa reagents as well as the centrally provided reagent, a modified STA® Rotachrom® assay. A calibration curve was produced each day, and the day-to-day precision was evaluated by testing three human plasma controls. When using the local anti-factor Xa reagents, the mean rivaroxaban concentrations (measured/actual values) were: 17/20, 205/199 and 668/662 ng/ml, and the coefficient of variance (CV) was 37.0%, 13.7% and 14.1%, respectively. When the modified STA Rotachrom method was used, the measured/actual values were: 18/20, 199/199 and 656/662 ng/ml, and the CV was 19.1%, 10.9% and 10.0%, respectively. The results suggest that, by using rivaroxaban calibrators and controls, the anti-factor Xa chromogenic method is suitable for measuring a wide range of rivaroxaban plasma concentrations (20–660 ng/ml), which covers the expected rivaroxaban plasma levels after therapeutic doses.

 
  • References

  • 1 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.
  • 2 Hirsh J, Bauer KA, Donati MB. et al. Parenteral anticoagulants: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008; 133: 141S-159S.
  • 3 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: 514-521.
  • 4 Eriksson BI, Borris LC, Friedman RJ. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.. N Engl J Med 2008; 358: 2765-2775.
  • 5 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.
  • 6 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.
  • 7 Turpie AGG, Lassen MR, Davidson BL. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.. Lancet 2009; 373: 1673-1680.
  • 8 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
  • 9 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.. N Engl J Med 2011; 365: 883-891.
  • 10 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.. J Thromb Haemost. 2005 3. (Suppl 1): Abstract P1104
  • 11 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.
  • 12 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: 873-880.
  • 13 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: 335-344.
  • 14 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: 203-216.
  • 15 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: 1263-1271.
  • 16 Lindhoff-Last E, Samama MM, Ortel TL. et al. Assays for measuring rivaroxaban: their suitability and limitations.. Ther Drug Monit 2010; 32: 673-679.
  • 17 Perzborn E, Harwardt M, Samama M. Assessment of Factor Xa chromogenic assays for measuring the pharmacodynamics of rivaroxaban – an oral, direct Factor Xa inhibitor. J Thromb Haemost 2009; 7 (Suppl. 02) 379 Abstract PP-MO-185.
  • 18 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.
  • 19 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.
  • 20 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: 815-825.
  • 21 Samama MM, Le Flem L, Guinet C. et al. Suitability of chromogenic anti-FXa methods to measure rivaroxaban in human plasma. J Thromb Haemost 2009; 7 (Suppl. 02) 693 Abstract PP-WE-199.
  • 22 Kubitza D, Becka M, Mueck W. et al. Aspirin has no effect on the safety, tolerability, pharmacodynamics and pharmacokinetics of BAY 59–7939 – an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005 3. (Suppl 1): Abstract P1105.
  • 23 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: 549-558.
  • 24 Kubitza D, Becka M, Zuehlsdorf M. et al. No interaction between the novel, oral direct Factor Xa inhibitor BAY 59–7939 and digoxin. J Clin Pharmacol 2006; 46: 702 Abstract 11.
  • 25 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: 469-476.
  • 26 Kubitza D, Becka M, Mueck W. et al. Co-administration of rivaroxaban - a novel, oral, direct Factor Xa inhibitor - and clopidogrel in healthy subjects. Eur Heart J 2007; 28 (Suppl. 01) 189 Abstract P1272.
  • 27 Bayer Schering Pharma AG.. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2011 Available at: http://www.xarelto.com/scripts/pages/en/_global/download-media.php?media=/html/downloads/Xarelto_Summary_of_Product_Characteristics_Jan2011.pdf&tm=1309354217 Accessed September 6, 2011.
  • 28 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: 453-461.
  • 29 Bounameaux H, Reber G.. New oral antithrombotics: a need for laboratory monitoring. Against.. J Thromb Haemost 2010; 8: 627-630.
  • 30 Mismetti P, Laporte S.. New oral antithrombotics: a need for laboratory monitoring.. J Thromb Haemost 2010; 8: 621-626.
  • 31 Walenga JM, Hoppensteadt DA.. Monitoring the new antithrombotic drugs. Semin Thromb Hemost 2004; 30: 683-695.
  • 32 Samama MM, Guinet C.. Laboratory assessment of new anticoagulants. Clin Chem Lab Med 2011; 49: 761-772.
  • 33 Samama MM, Le Flem L, Guinet C. et al. Comparative responses of some clotting assays to fondaparinux, dabigatran and rivaroxaban. Pathophysiol Haemost Thromb 2008; 36 (Suppl. 01) P98-P99.
  • 34 Smith SA, Morrissey JH.. Thromboplastin composition affects the sensitivity of prothrombin time (PT) clotting tests to direct Factor Xa inhibitors. Blood (ASH Annual Meeting Abstracts) 2007; 110 Abstract 928.
  • 35 Tripodi A, Chantarangkul V, Guinet C. et al. The International Normalized Ratio calibrated for rivaroxaban has the potential to normalize prothrombin time results for rivaroxaban-treated patients: results of an in vitro study.. J Thromb Haemost 2011; 9: 226-228.
  • 36 Samama MM, Martinoli JL, Perzborn E. et al. Evaluation of rivaroxaban calibrators and controls and the prothrombin time for measuring rivaroxaban plasma concentrations. Hämostaseologie 2010; 30: A114 Abstract P17-21.
  • 37 Tripodi A.. Measuring the anticoagulant effect of direct Factor Xa inhibitors. Is the anti-Xa assay preferable to the prothrombin time test?. Thromb Haemost 2011; 105: 735-736.
  • 38 Bates SM, Weitz JI.. Coagulation assays. Circulation 2005; 112: e53-e60.
  • 39 Klaeffling C, Piechottka G, Daemgen-von Brevern G. et al. Development and clinical evaluation of two chromogenic substrate methods for monitoring fondaparinux sodium.. Ther Drug Monit 2006; 28: 375-381.
  • 40 Depasse F, Gerotziafas GT, Busson J. et al. Assessment of three chromogenic and one clotting assays for the measurement of synthetic pentasaccharide fondaparinux (Arixtra) anti-Xa activity.. J Thromb Haemost 2004; 2: 346-348.
  • 41 Karst A, Bakowski-Enzian B, Perzborn E. Monitoring of rivaroxaban: suitability of a well-established chromogenic anti-Factor Xa assay. J Thromb Haemost 2009; 7 (Suppl. 02) 372 Abstract PP-MO-162.
  • 42 Freyburger G, Macouillard G, Labrouche S. et al. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement.. Thromb Res 2011; 127: 457-465.