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.
Human Serum Albumin Human Plasma Venous Thromboembolism Antithrombin Fondaparinux
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Boneu B. New antithrombotic agents for the prevention and treatment of deep vein thrombosis. Haemostasis 1996; 26 Suppl. 4: 368–78PubMedGoogle Scholar
Lormeau JC, Herault JP, Gaich C, et al. Determination of the anti-factor Xa activity of the synthetic pentasaccharide SR90107A/ORG 31540 and of two structural analogues. Thromb Res 1997; 85: 67–75PubMedCrossRefGoogle Scholar
Walenga JM, Jeske WP, Bara L, et al. Biochemical and pharmacologic rationale for the development of a synthetic heparin pentasaccharide. Thromb Res 1997; 86: 1–36PubMedCrossRefGoogle Scholar
Amiral J, Bridley F, Wolf M, et al. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases. Thromb Haemost 1995; 73: 21–8PubMedGoogle Scholar
Gould K, Dembitizer AD, Doyle RL, et al. Low molecular weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800–9PubMedGoogle Scholar
Leyvraz PF, Bachmann F, Hoek J, et al. Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin. BMJ 1991; 303: 543–8PubMedCrossRefGoogle Scholar
Planès A, Vochelle N, Fagola M, et al. Comparison of two low-molecular-weight heparins for the prevention of postoperative venous thromboembolism after elective surgery. Reviparin Study group. Blood Coagul Fibrinolysis 1998; 9: 499–505PubMedCrossRefGoogle Scholar
Donat FA, Duret JP, Santoni A, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Pharmacokinet 2002; 41 Suppl. 2: 1–9CrossRefGoogle Scholar
Boneu B, Necciari J, Cariou R, et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107A/ Org31540) with high affinity to antithrombin III in man. Thromb Haemost 1995; 74: 1468–73PubMedGoogle Scholar
Turpie AG, Gallus AS, Hoek JA. Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep vein thrombosis after total hip replacement. N Engl J Med 2001; 344: 619–25PubMedCrossRefGoogle Scholar
Lassen MR. Efficacy of the first synthetic factor Xa inhibitor, pentasaccharide Org31540/SR90107A, versus low molecular weight heparin (LMWH) in the prevention of venous throm-boembolism (VTE) following elective hip replacement surgery: the Ephesus study [abstract]. Thromb Haemost 2001; 86 Suppl.: OC45Google Scholar
Bauer K. Efficacy of the first synthetic factor Xa inhibitor, pentasaccharide Org31540/SR90107A, versus low molecular weight heparin (LMWH) in the prevention of venous thromboembolism (VTE) following elective major knee surgery: the Pentamaks Study [abstract]. Thromb Haemost 2001; 86 Suppl.: OC46Google Scholar
Eriksson BI. Efficacy of the first synthetic factor Xa inhibitor, pentasaccharide Org31540/SR90107A, versus low molecular weight heparin (LMWH) in the prevention of venous thromboembolism (VTE) in the prevention of venous thromboembolism (VTE) following hip fracture surgery: the Penthifra Study [abstract]. Thromb Haemost 2001; 86 Suppl.: OC47Google Scholar
Eriksson BI, Bauer KA, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip fracture surgery. N Engl J Med 2001; 345: 1298–304PubMedCrossRefGoogle Scholar
Bauer KA, Eriksson BI, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305–10PubMedCrossRefGoogle Scholar
Barre J, Didey F, Delion F, et al. Problems in therapeutic drug monitoring: free drug level monitoring. Ther Drug Monit 1988; 10: 133–43PubMedCrossRefGoogle Scholar
Shah VP, Midha KK, Findlay JWA, et al. Bioanalytical method validation: a revisit with a decade of progress. Pharm Res 2000; 17: 1551–7PubMedCrossRefGoogle Scholar
Conard J, Brosstad F, Lie LM, et al. Molar antithrombin concentration in normal human plasma. Haemostasis 1983; 13: 363–8PubMedGoogle Scholar
Olson ST, Bjork I, Sheffer R, et al. Role of antithrombin-binding in heparin acceleration of antithrombin-proteinase reaction: resolution of the antithrombin conformational change contribution to heparin rate enhancement. J Biol Chem 1992; 267: 12528–38PubMedGoogle Scholar
Zitoun D, Bara L, Bloch MF, et al. Plasma TFPI activity after intravenous injection of pentasaccharide (PS) and unfractionated heparin in rabbits. Thromb Res 1994; 75: 577–80PubMedCrossRefGoogle Scholar