The Synthetic Pentasaccharide Fondaparinux Sodium Does Not Interact with Oral Warfarin
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Clin Pharmacokinet 2002; 41 Suppl. 2: 27-29 0312-5963/02/0002-0027/$25.00/0 © Adis International Limited. All rights reserved.
The Synthetic Pentasaccharide Fondaparinux Sodium Does Not Interact with Oral Warfarin1 Richard A. Faaij,1 Jacobus Burggraaf,1 Rik C. Schoemaker,1 Rik de Greef2 and Adam F. Cohen1 1 Centre for Human Drug Research, Leiden, The Netherlands 2 NV Organon, Oss, The Netherlands
Fondaparinux sodium, the first of a new class of antithrombotic agents, is a pure selective inhibitor of factor Xa that acts via antithrombin III (ATIII) and does not inhibit thrombin itself. The pharmacological effect of fondaparinux results in strong inhibition of thrombin generation.[1-3] The objectives of this study were to evaluate whether any pharmacokinetic and pharmacodynamic interactions occurred between fondaparinux sodium 4mg administration at steady state and oral warfarin administered as a high-dose regimen to mimic the situation in clinical practice when patients undergoing treatment for venous thromboembolism receive concomitant parenteral and oral anticoagulants. 1. Patients and Methods This was a randomised, three-way crossover, placebo-controlled, double-blind study with a 2-week washout period. Twelve healthy males aged 19 to 27 years received fondaparinux sodium only, oral warfarin only (Coumadin®)2, or the combination of fondaparinux sodium and warfarin. The fondaparinux sodium-only treatment was five 4mg 1 The data in this Short Communication have been presented in full in de Greef R, Faaij RA, Burggraaf J, et al. Absence of an interaction between synthetic pentasaccharide fondaparinux and oral warfarin. British Journal of Clinical Pharmacology 2002; 54 (3): 304-8. This article is published with the permission of Blackwell Science Ltd.
subcutaneous injections at 24-hour intervals and oral placebo tablets with the fourth and fifth injections. The warfarin-only treatment was five subcutaneous placebo (0.9% saline) injections at 24hour intervals. Oral warfarin 15mg was added to the fourth placebo injection, and warfarin 10mg was given with the fifth placebo injection. The combination treatment was five subcutaneous injections of fondaparinux sodium 4mg and oral warfarin 15mg and 10mg given concomitantly with, respectively, the fourth and fifth injections of fondaparinux sodium. All subjects received a single 10mg dose of vitamin K at 36 hours after the last drug administration to reverse any residual warfarin effect. In the combination treatment arm, the high-dose regimen of warfarin was given on day 4 and day 5, when fondaparinux sodium reached steady state. Fondaparinux sodium concentrations in plasma were assessed using a validated chromogenic assay (unpublished data, Organon), based on the inhibition of factor Xa by the ATIII-fondaparinux sodium complex. The lower limit of quantification was 0.0251 mg/L. The activated partial thromboplastin time (aPTT) and prothrombin time (PT) assays were performed using standard procedures[4] with an STA coagulation analyser (Stago, Asnières, France) with a sing
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