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Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins.

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, antithrombin-depleted plasma or purified human plasma proteins, including antithrombin, alpha1-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 B(max) (binding capacity) and K(D )(dissociation constant) were similar for human plasma (B(max) = 2072 nmol/L, K(D) = 28 nmol/L) and purified ATIII (B(max) = 1627 nmol/L and K(D) = 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 alpha1-acid glycoprotein displacement is unlikely.

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

Paolucci F,Claviés MC,Donat F,Necciari J

doi

10.2165/00003088-200241002-00002

keywords:

subject

Has Abstract

pub_date

2002-01-01 00:00:00

pages

11-8

eissn

0312-5963

issn

1179-1926

pii

410002

journal_volume

41 Suppl 2

pub_type

杂志文章

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Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins.