Absence of an interaction between the synthetic pentasaccharide fondaparinux and oral warfarin

Abstract

Aims: To investigate the pharmacokinetic and pharmacodynamic interaction of the antithrombotic pentasaccharide fondaparinux (Org31540/SR90107A), given subcutaneously, and oral warfarin in healthy subjects.

Methods: This study was performed according to a randomised, three-way cross-over, placebo-controlled, double-blind design in 12 healthy male subjects. The treatment consisted of five subcutaneous (s.c.) injections of fondaparinux (4 mg) or placebo at 24 h intervals. Oral dosing of warfarin or placebo was added to the fourth (15 mg) and fifth (10 mg) s.c. injection. Blood samples for pentasaccharide assay, PT and APTT were drawn before the first s.c. dose of the pentasaccharide and over a 6 day period thereafter.

Results: Fondaparinux administered to healthy male volunteers alone or in combination with oral warfarin was well tolerated and no serious adverse events were observed. No differences were found in the AUC (43 vs 44 mg l(-1) h), Cmax (645 vs 678 ng ml(-1)) or elimination half-life (13.8 vs 14.1 h) of fondaparinux between the pentasaccharide-only and the combination treatment. The effect of warfarin on PT (mean maximal increase: 8.2 s.) was not influenced by the presence of the pentasaccharide (mean maximal increase in PT: 9.1 s.). After all treatments a small rise in APTT was seen. No further differences could be detected in the pharmacodynamic parameters following the three treatments.

Conclusions: The coadministration of warfarin did not influence the pharmacokinetics of fondaparinux in healthy subjects. PT can still be used to monitor the effect of oral anticoagulants during the switch from antithrombotic treatment with pentasaccharide to full oral anticoagulant therapy.

Figure 1

Schematic overview of the study design; closed symbols indicate active treatment pentasaccharide (arrows) or warfarin (circles) while open symbols indicate corresponding placebo treatment. K indicates vit. K administration.

Figure 2

Mean pentasaccharide plasma concentration-time curves (a), mean PT values (b) and mean APTT values (c) per treatment (▪ pentasaccharide; ▴ pentasaccharide plus warfarin; • warfarin). The s.c. pentasaccharide injections and oral warfarin adminstrations are indicated.The arrow indicates the timepoint at which vitamin K was administered.