Anticoagulant effects of idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations from the van Gogh trials.

Abstract

AIM:

To gather information on anticoagulant effects after the termination of long-term therapy with idraparinux.

METHODS:

The anticoagulant effects of idraparinux, a synthetic polymethylated analogue of its pentasaccharide, were analysed in 23 patients after termination of a 6- or 12-month therapy period for the prevention of recurrent venous thromboembolism (VTE). Plasma samples of patients initially randomized to 2.5 mg idraparinux (normal creatinine clearance) or 1.5 mg idraparinux (creatinine clearance < 30 ml/min) were investigated in the van Gogh trials. At 3-month intervals for up to 15 months following the termination of the therapy, the factor Xa-specific S2222 chromogenic substrate (aXa) assay and Heptest were used to determine various pharmacokinetic parameters and prothrombin-induced clotting time (PiCT), activated partial thromboplastin time (aPTT) and prothrombin time (PT) were determined.

RESULTS:

Based on the aXa assay and Heptest, the half lives (t1/2) were 60.2 days and 107.7 days (p < 0.0001), maximum drug concentrations (Cmax) were 0.30 and 0.39 microg/l (p = 0.0016), areas under the activity time curve (AUC) were 33.7 and 38.0 microg/l per day (p = 0.0002), plasma clearances were 0.09 and 0.06 ml/min (p < 0.0001), mean residence times (MRT) were 75.4 and 121.9 (p < 0.0001) and volumes of distribution (Vdiss) were 7.4 and 8.61 (p = 0.1336), respectively. After 12 months of treatment (n = 18), the S2222 and Heptest results showed significantly higher Cmax and AUC, lower Vdiss and clearance and unchanged t1/2 and MRT values compared to 6 months of treatment (n = 5). The PiCT was prolonged for a period of 9 months. Coagulation times of aPTT and PT were not influenced. The results of these parameters did not differ between 12 and 6 months of treatment.

CONCLUSION:

The data support reports on a non-ionic binding of idraparinux to antithrombin and other proteins. We suggest that these findings may explain some of the findings of the van Gogh Extension trial.

• Authors: Job Harenberg, Ingrid Jörg, Yvonne Vukojevic, Gerd Mikus, Christel Weiss
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 64 Issue 6 Pg. 555-63 (Jun 2008) ISSN: 0031-6970 [Print] Germany
• PMID: 18283446 (Publication Type: Journal Article, Review)

Chemical References

• Anticoagulants
• Oligosaccharides
• idraparinux

Topics

• Anticoagulants (pharmacology)
• Half-Life
• Humans
• Oligosaccharides (pharmacokinetics, pharmacology, therapeutic use)
• Randomized Controlled Trials as Topic
• Recurrence
• Venous Thromboembolism (prevention & control)