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.
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 heparinenoxaparin, 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.
Authors: V P Shah; K K Midha; J W Findlay; H M Hill; J D Hulse; I J McGilveray; G McKay; K J Miller; R N Patnaik; M L Powell; A Tonelli; C T Viswanathan; A Yacobi Journal: Pharm Res Date: 2000-12 Impact factor: 4.200
Authors: B Boneu; J Necciari; R Cariou; P Sié; A M Gabaig; G Kieffer; J Dickinson; G Lamond; H Moelker; T Mant Journal: Thromb Haemost Date: 1995-12 Impact factor: 5.249
Authors: François Donat; Jean Pierre Duret; Alix Santoni; Roger Cariou; José Necciari; Harry Magnani; Rik de Greef Journal: Clin Pharmacokinet Date: 2002 Impact factor: 6.447
Authors: François Donat; Jean Pierre Duret; Alix Santoni; Roger Cariou; José Necciari; Harry Magnani; Rik de Greef Journal: Clin Pharmacokinet Date: 2002 Impact factor: 6.447
Authors: Genmin Lu; Francis R DeGuzman; Stanley J Hollenbach; Mark J Karbarz; Keith Abe; Gail Lee; Peng Luan; Athiwat Hutchaleelaha; Mayuko Inagaki; Pamela B Conley; David R Phillips; Uma Sinha Journal: Nat Med Date: 2013-03-03 Impact factor: 53.440