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


CONCLUSIONS
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.
Paolucci
Francis
F
Sanofi-Synthelabo Groupe, Montpellier, France. Francis.Paolucci@sanofi-synthelabo.com
Claviés
Marie-Christine
MC
Donat
François
F
Necciari
José
J
D000990:Antithrombin III / Q000378:metabolism*; D001798:Blood Proteins; D005343:Fibrinolytic Agents / Q000097:blood / Q000378:metabolism*; D000077425:Fondaparinux; D006801:Humans; D066298:In Vitro Techniques; D011134:Polysaccharides / Q000097:blood / Q000378:metabolism*; D011485:Protein Binding
D001798:Blood Proteins; D005343:Fibrinolytic Agents; D011134:Polysaccharides; D000990:Antithrombin III; D000077425:Fondaparinux