The pharmacokinetics of fondaparinux sodium in healthy volunteers.

Abstract

Fondaparinux sodium is the first in a new class of synthetic factor Xa inhibitors that binds reversibly with high affinity to antithrombin III. It has been investigated for the prevention and treatment of arterial and venous thrombotic disorders and approved for use at a dose of 2.5mg once daily in the prevention of venous thromboembolism in major orthopaedic surgery. The pharmacokinetics of fondaparinux sodium were determined in eight studies in young and elderly healthy volunteers. After a 2.5mg subcutaneous dose to young volunteers, absolute bioavailability was 100% and absorption was rapid and complete [peak plasma concentration (C(max)) 0.34 mg/L occurred at approximately 2 hours]. Within- and total-subject variability estimates were small: 5.5 and 11.6%, respectively, for C(max )and 4.4 and 17.5% for area under the concentration-time curve (AUC). Steady state was obtained after the third or fourth once-daily dose, with a 1.3-fold increase in C(max) and AUC. Distribution volume (7 to 11L) was limited to blood volume. There was no evidence of metabolism. Fondaparinux sodium was almost completely excreted in urine as unchanged compound (64 to 77% of the dose was recovered at 72 hours after administration). Plasma clearance was 5.1 to 7.9 ml/min, renal clearance 4.0 to 7.9 ml/min, and the terminal half-life was 17 hours in young volunteers and 21 hours in elderly volunteers. Pharmacokinetics of fondaparinux sodium were linear in the range 2 to 8mg subcutaneously and 2 to 20mg intravenously. Pharmacokinetics observed in healthy elderly volunteers were consistent with findings in young male volunteers. The favourable pharmacokinetic profile of fondaparinux sodium is likely to play an important role in the major advance that the drug represents in the prevention and treatment of thrombotic disorders.