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Clinical Pharmacokinetics

, Volume 41, Supplement 2, pp 11–18 | Cite as

Fondaparinux Sodium Mechanism of Action

Identification of Specific Binding to Purified and Human Plasma-Derived Proteins
  • Francis Paolucci
  • Marie-Christine Claviés
  • François Donat
  • José Necciari
Original Research Article

Abstract

Background: Fondaparinux sodium is a novel antithrombotic agent, the first of a new class of selective factor Xa inhibitors. It has favourable pharmacokinetics including 100% bioavailability, low variability and a mean terminal half-life of 17 hours for young and 21 hours for elderly healthy volunteers, enabling once-daily administration. Studies on the prevention of venous thromboembolism (VTE) after orthopaedic surgery demonstrated significantly improved efficacy over the low-molecular-weight heparin enoxaparin, with a >50% reduced risk of VTE and a similar safety profile.

Objective:To investigate the in vitro binding of fondaparinux sodium to purified antithrombin III (ATIII) and other plasma proteins.

Methods: Fondaparinux sodium was incubated with human plasma, anti-thrombin-depleted plasma or purified human plasma proteins, including anti-thrombin, α1-acid glycoprotein, serum albumin and immunoglobulin. Non-protein-bound fondaparinux sodium was determined using a validated chromogenic assay method, enabling the calculation of the free fraction of fondaparinux sodium and its binding parameters.

Results: At steady state, fondaparinux sodium at therapeutic concentrations [i.e. those attainable in the prevention (0.14 to 0.50 mg/L) and treatment (up to approximately 2 mg/L) of VTE] was extensively bound (>97%) to plasma proteins and specifically bound (>94%) to purified ATIII. The specific binding parameters Bmax (binding capacity) and KD (dissociation constant) were similar for human plasma (Bmax = 2072 nmol/L, KD = 28 nmol/L) and purified ATIII (Bmax = 1627 nmol/L and KD = 32 nmol/L). There was no specific binding of fondaparinux sodium to other purified plasma proteins.

Conclusion: At clinically relevant concentrations, fondaparinux sodium is highly and specifically bound to ATIII in human plasma, suggesting that potential interaction with drugs via albumin or α1-acid glycoprotein displacement is unlikely.

Keywords

Human Serum Albumin Human Plasma Venous Thromboembolism Antithrombin Fondaparinux 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Francis Paolucci
    • 1
  • Marie-Christine Claviés
    • 1
  • François Donat
    • 1
  • José Necciari
    • 1
  1. 1.Sanofi-Synthelabo GroupeMontpellier CedexFrance

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