PDF herunterladen
Thromb Haemost 2009; 102(05): 811-815
DOI: 10.1160/TH09-08-0555
Theme Issue Article
Schattauer GmbH

Development of idraparinux and idrabiotaparinux for anticoagulant therapy

Job Harenberg
1   Clinical Pharmacology, Faculty of Medicine Mannheim, Ruprecht-Karls University Heidelberg, Mannheim, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 12. August 2008

Accepted after major revision: 04. Oktober 2009

Publikationsdatum:
27. November 2017 (online)

Auch verfügbar auf
   Lizenzen und Reprints

Summary

Idraparinux is an analogue of fondaparinux binding with high affinity to antithrombin. It was designed for weekly, rather than daily, administration, with an exceptionally long half-life. One potential problem with small heparin-like fragments of this type is the difficulty of neutralising excessive activity in the case of sideeffects or overdose. The efficacy of idraparinux was was proven in clincial studies with patients suffering from venous thromboembolism (VTE) or atrial fibrillation. Due to major bleeding events during treatment for more than six months the development of idraparinux was stopped. Idrabiotaparinux has an attached biotin moiety at the non-reducing end unit, which allows its neutralisation with avidin, an egg-derived protein with low antigenicity. This compound is currently investigated in clinical trials for prevention of recurrent VTE in patients with acute pulmonary embolism. The future of idrabiotaparinux depends also on the safety and efficacy of avidin.

Keywords

Idraparinux - idrabiotaparinux - thrombosis - atrial fibrillation
 

  • References

  • 1 Kearon C, Kahn SR, Agnelli G. et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 445S-454S.
    PubMedSuche in Google Scholar
  • 2 Warkentin TE, Greinacher A, Koster A. et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 340S-380S.
    CrossrefPubMedSuche in Google Scholar
  • 3 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.
    CrossrefPubMedSuche in Google Scholar
  • 4 Singer DE, Albers GW, Dalen JE. et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 546S-5592S.
    CrossrefPubMedSuche in Google Scholar
  • 5 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.
    CrossrefPubMedSuche in Google Scholar
  • 6 Koopman MM, Büller HR. Short-and long-acting synthetic pentasaccharides. J Intern Med 2003; 254: 335-342.
    CrossrefPubMedSuche in Google Scholar
  • 7 Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2008; 133: 234S-256S.
    CrossrefPubMedSuche in Google Scholar
  • 8 Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa. Semin Thromb Hemost 2008; 34: 39-57.
    Thieme ConnectPubMedSuche in Google Scholar
  • 9 Prandoni P, Tormene D, Perlati M. et al. Idraparinux: review of its clinical efficacy and safety for prevention and treatment of thromboembolic disorders. Expert Opin Investig Drugs 2008; 17: 773-777.
    CrossrefPubMedSuche in Google Scholar
  • 10 Herbert JM, Hérault JP, Bernat A. et al. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide. Blood 1998; 91: 4197-4205.
    PubMedSuche in Google Scholar
  • 11 Organon, Sanofi-Synthélabo. Idraparinux sodium. Drug Data Rep 2003; 25: 332.
    PubMedSuche in Google Scholar
  • 12 Van Amsterdam RGM, Burggraaf J, Borm GF. et al. A phase I multiple dose study to investigate the safety, tolerance and pharmacokinetics of 10mg S.C. SanOrg34006 in male and female volunteers with a history of VTE, recently discharged from oral anticoagulant treatment. Clinical Trial Report on Protocol 64703. NV Organon. R&DRR NL0028967.
    PubMed
  • 13 Faaij RA, Burggraaf J, Schoemaker RC. et al. A phase I single rising dose study to investigate the safety, tolerance and pharmacokinetics of subcutaneous SANORG 34006 in healthy male and female elderly volunteers. Thromb Haemost. 1999 Suppl: Abstract 1547.
    PubMedSuche in Google Scholar
  • 14 Faaij RA, Burggraaf J, Schoemaker RC. et al. A phase I single rising dose study to investigate the safety, tolerance and pharmacokinetics of SANORG 34006 in healthy young male volunteers. Thromb Haemost. 1999 Suppl: Abstract 2709.
    PubMedSuche in Google Scholar
  • 15 Idraparinux sodium. Drug Data Report. 2003; 25: 332.
    PubMedSuche in Google Scholar
  • 16 PERSIST investigators. A novel long-acting synthetic factor Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis. A Phase II evaluation. J Thromb Haemost 2004; 02: 47-53.
    CrossrefPubMedSuche in Google Scholar
  • 17 Harenberg J, Jörg I, Vukojevic Y. et al. Anticoagulant effects of idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations from the van Gogh trials. Eur J Clin Pharmacol 2008; 64: 555-563.
    CrossrefPubMedSuche in Google Scholar
  • 18 Veyrat-Follet C, Vivier N, Trellu M. et al. The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trials. J Thromb Haemost 2009; 07: 559-565.
    CrossrefPubMedSuche in Google Scholar
  • 19 Ma Q, Fareed J. Idraparinux sodium. Sanofi-Aventis. IDrugs 2004; 07: 1028-1034.
    PubMedSuche in Google Scholar
  • 20 Bijsterveld NR, Vink R, Van Arken BE. et al. Recombinant factor VIIa reverses the anticoagulant effect of the longacting pentasaccharide idraparinux in healthy volunteers. Br J Haematol 2004; 124: 653-658.
    CrossrefPubMedSuche in Google Scholar
  • 21 The van Gogh Investigators. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007; 357: 1094-1104.
    CrossrefPubMedSuche in Google Scholar
  • 22 The van Gogh Investigators. Extended prophylaxis of venous thromboembolism with idraparinux. N Engl J Med 2007; 357: 1105-1112.
    CrossrefPubMedSuche in Google Scholar
  • 23 Harenberg J, Weiss C, Mikus G. et al. Long elimination half life of idraparinux after termination of therapy explains bleeding in the van Gogh trials. J Thromb Haemost 2008; 06: 890-892.
    CrossrefPubMedSuche in Google Scholar
  • 24 The Amadeus Investigators. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomized, open-label, non-inferiority trial. Lancet 2008; 371: 315-321.
    CrossrefPubMedSuche in Google Scholar
  • 25 Patents EP 1 322 673 B1/US 6,844,329 B2. http://www.epo.org/ patents/patent-information/european-patent-documents/publicationserver.html
    PubMed
  • 26 Kang YS, Saito Y, Pardridge WM. Pharmacokinetics of [3H]biotin bound to different avidin analogues. J Drug Target 1995; 03: 159-165.
    CrossrefPubMedSuche in Google Scholar
  • 27 Wilchek M, Bayer EA. The avidin-biotin complex in bioanalytical applications. Anal Biochem 1988; 171: 1-32.
    CrossrefPubMedSuche in Google Scholar
  • 28 Muus CJ, Azar HA. Application of immunochemistry to the diagnosis of human neoplasms in routine histologic sections. Diagn Immunol 1986; 04: 125-139.
    PubMedSuche in Google Scholar
  • 29 Huntington JA, McCoy A, Belzar KJ. et al. The conformational activation of antithrombin. A 2.85-A structure of a fluorescein derivative reveals an electrostatic link between the hinge and heparin binding regions. J Biol Chem 2000; 275: 15377-15383.
    CrossrefPubMedSuche in Google Scholar
  • 30 Savi P, Herault JP, Duchaussoy P. et al. Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy. J Thromb Haemost 2008; 06: 1697-1706.
    CrossrefPubMedSuche in Google Scholar
  • 31 Burkhart KK, Britt AM. Reversal of toxicity using avidin-based hemoperfusion: a model system in rats using biotinylated melittin. Pharmacology 1995; 50: 307-312.
    CrossrefPubMedSuche in Google Scholar
  • 32 Stoldt HS, Aftab F, Chinol M, Paganelli G, Luca F, Testori A, Geraghty JG. Pretargeting strategies for radio-immunoguided tumour localisation and therapy. Eur J Cancer 1997; 33: 186-192.
    CrossrefPubMedSuche in Google Scholar
  • 33 Trellu M, Perez Y, Ortiz J. et al. Bioequipotency of idraparinux and biotinylated idraparinux after single dose in healthy subjects. J Thromb Haemost 2007; 05: P-T-678.
    PubMedSuche in Google Scholar
  • 34 Buller HR, Destors JM, Gallus AS. et al. Idrabiotaparinux, a Biotinylated Long-Acting Anticoagulant, in the Treatment of Deep Venous Thrombosis (EQUINOX Study): Safety, Efficacy, and Reversibility by Avidin. Blood 2008; 112: 18 Abstract 32..
    PubMedSuche in Google Scholar
  • 35 Turpie AG. Fondaparinux: a factor Xa inhibitor for antithrombotic therapy. Expert Opin Pharmacother 2004; 05: 1373-1384.
    CrossrefPubMedSuche in Google Scholar
  • 36 de Kort M, Buijsman RC, van Boeckel CA. Synthetic heparin derivatives as new anticoagulant drugs. Drug Discov Today 2005; 10: 769-779.
    CrossrefPubMedSuche in Google Scholar