REOPRO Solution for injection or infusion Ref.[2442] Active ingredients: Abciximab

Pharmacotherapeutic group: antithrombotic agents, platelet aggregation inhibitors excl. heparin
ATC code: B01AC13

Mechanism of action

ReoPro is the Fab fragment of the chimeric monoclonal antibody 7E3. It is directed against the glycoprotein (GP) IIb/IIIa (α_IIbβ₃) receptor located on the surface of human platelets. ReoPro inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. ReoPro also binds to the vitronectin receptor (α_vβ₃) found on platelets and endothelial cells.

The vitronectin receptor mediates the pro-coagulant properties of platelets and proliferative properties of vessel wall endothelial and smooth muscle cells. Because of its dual specificity, ReoPro more effectively blocks the burst of thrombin generation that follows platelet activation than agents which inhibit GPIIb/IIIa alone.

Clinical efficacy

In a phase I clinical study intravenous administration in humans of single bolus doses of ReoPro from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function as measured by ex vivo platelet aggregation in response to adenosine diphosphate (ADP) or by prolongation of bleeding time. At the two highest doses (0.25 and 0.30 mg/kg) at 2 hours post injection, over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 µM ADP was almost abolished. Published data have shown that this level of platelet inhibition was established within 10 minutes of administration. In the phase I study, the median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately 5 minutes. The 80% level of receptor blockade was selected as a target for pharmacological efficacy because animal models of severe coronary stenosis have shown that platelet inhibition associated with this degree of blockade prevents platelet thrombosis.

Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 µg/min for periods of 12 to 96 hours produced sustained high-grade GPIIb/IIIa receptor blockade (≥80%) and inhibition of platelet function (ex vivo platelet aggregation in response to 20 µM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Equivalent results were obtained when a weight adjusted infusion dose (0.125 µg/kg/min to a maximum of 10 µg/min) was used in patients up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 µg/min infusion for 24 hours showed a similar initial receptor blockade and inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. Although low levels of GPIIb/IIIa receptor blockade are present for more than 10 days following cessation of the infusion, platelet function typically returned to normal over a period of 24 to 48 hours.

In clinical studies, ReoPro has demonstrated marked effects in reducing the thrombotic complications of coronary interventions such as balloon angioplasty, atherectomy and stent placement. These effects were observed within hours of the intervention and sustained for 30 days in the EPIC, EPILOG, EPISTENT and CAPTURE studies. In the EPIC study, which enrolled high-risk angioplasty patients, and in the two intervention studies which enrolled mainly high-risk angioplasty patients EPILOG (36% low risk and 64% high risk) and EPISTENT (27% low risk and 73% high risk), the infusion dose was continued for 12 hours after the procedure and the reduction in the composite endpoint of death, MI or repeat intervention was sustained for the period of follow up, 3 years (EPIC) 1 year (EPILOG) and 1 year (EPISTENT), respectively. In the EPIC study, the reduction in the composite endpoint was derived primarily from the effect on MI and both urgent and non-urgent revascularizations. In the EPILOG and EPISTENT studies, the reduction in the composite endpoint was derived primarily from the effect on non-Q-wave MI (identified by cardiac enzyme increases) and urgent revascularizations. In the CAPTURE study in patients with unstable angina not responding to medical therapy, ReoPro was administered as a bolus plus infusion starting up to 24 hours before the procedure until 1 hour after completion of the procedure. This regimen demonstrated stabilization of patients prior to angioplasty, as shown for example by a reduction in MIs, and the reduction in thrombotic complications was sustained at the 30-day endpoint but not at 6 months.