Nonimmunogenicity of eptifibatide, a cyclic heptapeptide inhibitor of platelet glycoprotein IIb-IIIa.

Inhibitors of platelet glycoprotein (GP) IIb-IIIa have been demonstrated to be effective in controlling acute cardiac complications in patients presenting with acute ischemic coronary syndromes (AICS). Since patients with atherosclerotic coronary vascular disease may present with AICS on multiple occasions, it is important to have documented evidence that novel antithrombotic agents are nonimmunogenic and thus safe for repeated administration. Eptifibatide (Integrilin) is a cyclic heptapeptide inhibitor that contains a modified lysine-glycine-aspartic acid sequence that recognizes the binding site of platelet GP IIb-IIIa, resulting in potent and selective inhibition of its binding to fibrinogen. An enzyme-linked immunosorbent assay sensitive to all classes of immunoglobulins was developed to test the immunogenicity of eptifibatide in humans. In two clinical studies, Integrilin to Minimize and Prevent Acute Coronary Thrombosis (IMPACT) and IMPACT II, samples were obtained from 414 patients undergoing coronary angioplasty to determine anti-eptifibatide antibodies at baseline and 30 days after treatment. In a separate clinical pharmacology study, 28 healthy volunteers received 2 infusions of eptifibatide 28 days apart and were monitored at baseline (immediately before the first infusion), at 28 days (immediately before the second infusion), and at 42, 56, 84, and 112 days after enrollment to monitor for an anamnestic anti-eptifibatide response. Eptifibatide administration did not result in an antibody response in any of the 3 studies, even after repeated administration. Eptifibatide represents a potent, specific inhibitor of the platelet GP IIb-IIIa complex that has not been observed to be immunogenic in clinical studies and is thus safe for repeated administration. This finding suggests that small, peptide-based therapeutic agents, which are becoming increasingly common, may be used in humans without inciting an immune response.