Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy

Abstract

To cite this article: Savi P, Herault JP, Duchaussoy P, Millet L, Schaeffer P, Petitou M, Bono F, Herbert JM. Reversible biotinylated oligosaccharides:a new approach for a better management of anticoagulant therapy. J Thromb Haemost 2008; 6: 1697-706.Summary. Objective: In order to obtain a neutralizable antithrombotic, a chimeric molecule (SSR126517E) containing the sequence of a long-lasting antithrombin (AT)-dependent anti-factor Xa pentasaccharide, idraparinux, linked to a biotin molecule was synthesized and tested for anticoagulant and antithrombotic activity. Methods: SSR126517E was tested in several models in vitro and in vivo for its pharmacological properties as well as its ability to be neutralized by avidin. Results: SSR126517E displayed exactly the same properties as idraparinux. In vitro, SSR126517E had a very high affinity for AT (K d < 1 nM) and showed a potent anti-FXa effect and inhibition of thrombin generation with IC 50 values similar to those of idraparinux. Ex vivo, after intravenous administration to rats, SSR126517E produced a potent and long-lasting antiFXa effect comparable to that obtained with idraparinux; as with idraparinux, the subcutaneous bioavailability was 100%. In vivo, SSR126517E was a potent antithrombotic in rat and mouse venous and arterial thrombosis models. Direct comparison in rats showed that SSR126517E was as active as idraparinux, when administered at the same molar dose. Furthermore, injection of avidin triggered the immediate elimination of SSR126517E from the bloodstream, resulting in complete neutralization of the antithrombotic activity of SSR126517E. Conclusions: These results show for the first time that coupling an oligosaccharide with biotin has no effect on the formerÕs pharmacokinetic and pharmacologic properties and renders neutralization easy by injection of avidin.

New Anticoagulants

“…Designed to be more specific for fXa than LMWH, AVE5026, an ultralow-molecular-weight heparin, mainly targets fXa 11 ; idrabiotaparinux, a synthetic pentasaccharide, 12 and otamixaban 13 selectively target fXa; and RB006, an anticoagulant RNA aptamer, 14 specifically targets factor IXa. All of the new parenteral agents have a rapid onset of action and produce a predictable anticoagulant effect, which, in the case of idrabiotaparinux and RB006, can be rapidly neutralized by intravenous administration of avidin, a biotin-binding protein, or RB007, a complementary aptamer, respectively.…”

“…12 Consequently, idrabiotaparinux is given subcutaneously on a once-weekly basis. The drug is excreted unchanged by the kidneys.…”

Specificity and selectivity profile of EP217609: a new neutralizable dual-action anticoagulant that targets thrombin and factor Xa

“…Notably, avidin binding to EP217609 was found to cause a large loss in inhibitor potency (100-fold increase in K I for thrombin and 20-to 30-fold increase in the K D for antithrombin binding), contributing to an immediate neutralization of the drug's activity in addition to the indirect neutralization caused by avidin accelerating its clearance. 15,35 Phase 1 clinical studies in humans have indeed shown that administration of avidin triggers a rapid and irreversible neutralization of EP217609 without rebound effect. 18 The selectivity of EP217609 as a direct thrombin inhibitor largely derives from the extremely high affinity of the ␣-NAPAPlike moiety for thrombin (K I ϭ 30-40pM), which ranks among the highest-affinity direct thrombin inhibitors known.…”

Recent pharmacological advances for treating venous thromboembolism: are we witnessing the demise of warfarin?

“…It has a half-life of 130 h. 20 This permits once-weekly subcutaneous administration. The advantage of idrabiotaparinux over idraparinux is that it contains a biotin moiety which permits rapid reversal of anticoagulant action with intravenous avidin as the biotin-avidin complex terminates the drug action.…”

“…The advantage of idrabiotaparinux over idraparinux is that it contains a biotin moiety which permits rapid reversal of anticoagulant action with intravenous avidin as the biotin-avidin complex terminates the drug action. 20 In a multicentre trial, patients with an objectively confirmed PE received 5-10 days treatment with enoxaparin before being randomly allocated to treatment with idrabiotaparinux given once weekly or to the group treated conventionally with warfarin for three to six months. 21 Outcome was assessed at 99 days after randomization.…”