Bivalirudin

Absorption

Following intravenous administration, bivalirudin exhibits linear pharmacokinetics. The mean steady state concentration is 12.3 +/- 1.7mcg/mL after administration of an intravenous bolus of 1mg/kg followd by a 2.5mg/kg/hr intravenous infusion given over 4 hours.

Toxicity

Based on a study by Gleason et al., the no-observed-adverse-effect level (NOAEL) for bivalirudin, administered to rats via intravenous infusion over a 24-hour period, was 2000 mg/kg/24 h.

Description

Bivalirudin was launched in New Zealand as an anticoagulant for i.v. treatment of patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. Bivalirubin is a synthetic 20 amino acid peptide rationally modeled on hirudin (residues 53- 64), the most potent and specific naturally-occuring known inhibitor of thrombin, the enzyme that plays a key role in hemostasis and blood clot formation. This peptide is a direct thrombin inhibitor that maintains the unique bivalent binding properties of hirudin to the catalytic site and to the fibrin-recognition exosite of the enzyme, so acting directly on thrombin with high affinity and specificity. In vitro studies demonstrated that alpha- and zeta-thrombins, both with the higher fibrinogen-procoagulant activities, were inhibited. In rats receiving high doses of bivalirudin, the platelet deposition in carotide was reduced by 63% compared to controls. The results of clinical studies, conducted only in patients receiving concomitant aspirin, suggested that the use of bivalirudin was more efficacious and more predictable than unfractionated heparin, with fewer bleeding complications. Despite some unresolved developmental issues, the attractive properties of this novel agent could make it a useful alternative to heparin in a variety of coagulation disorders.

The Uses of Bivalirudin

Anticoagulant; antithrombotic.

Indications

For treatment of heparin-induced thrombocytopenia and for the prevention of thrombosis. Bivalirudin is indicated for use in patients undergoing percutaneous coronary intervention (PCI), in patients at moderate to high risk acute coronary syndromes due to unstable angina or non-ST segment elevation in whom a PCI is planned.

Background

Bivalirudin is a synthetic 20 residue peptide (thrombin inhibitor) which reversibly inhibits thrombin. Once bound to the active site, thrombin cannot activate fibrinogen into fibrin, the crucial step in the formation of thrombus. It is administered intravenously. Because it can cause blood stagnation, it is important to monitor changes in hematocrit, activated partial thromboplastin time, international normalized ratio and blood pressure.

Pharmacokinetics

Bivalirudin mediates an inhibitory action on thrombin by directly and specifically binding to both the catalytic site and anion-binding exosite of circulating and clot-bound thrombin. The action of bivalirudin is reversible because thrombin will slowly cleave the thrombin-bivalirudin bond which recovers the active site of thrombin.

Metabolism

80% proteolytic cleavage