CLINICAL-PHARMACOLOGY OF EPTIFIBATIDE

Activation of receptor function of platelet membrane glycoprotein (GP) IIb-IIIa leads to the binding of fibrinogen and is the final common p athway to platelet aggregation. Platelet aggregates provide the struct ural basis tor coronary thrombosis, a major cause of ischemic heart di sease. GP IIb-IIIa has a narrow tissue distribution, being found only on platelets and their progenitors, and inhibition of its receptor fun ction has emerged as a promising new therapeutic strategy for manageme nt of acute ischemic coronary syndromes and acute ischemic complicatio ns of percutaneous coronary interventions. Eptifibatide (INTEGRILIN) i s a cyclic heptapeptide inhibitor of GP IIb-IIIa, with an active pharm acophore that is derived from the structure of barbourin, a GP IIb-III a inhibitor from the venom of the southeastern pigmy rattlesnake. Like barbourin, eptifibatide is a specific and robust inhibitor of the GP IIb-IIIa receptor function, having a low affinity for other integrins and strongly preventing platelet aggregation. Preclinical pharmacologi c studies have established that eptifibatide can inhibit thrombosis ef fectively, with only modest effects on bleeding time measurements. Pha rmacokinetic and pharmacodynamic studies in both animal models and hum ans have shown that the antiplatelet effect of eptifibatide has a rapi d onset of action and that the drug has a short plasma half-life. Furt hermore, the rapid reversibility of action of eptifibatide, exemplifie d by an anti-hemostatic effect limited to the period of drug administr ation, was apparent in both healthy volunteers and patients with ische mic heart disease. In clinical trials, eptifibatide has not been found to be immunogenic or to induce thrombocytopenia. These studies have l ed to the evaluation of eptifibatide in the pivotal Integrilin to Mini mize Platelet Aggregation and Coronary Thrombosis (IMPACT II) trial, w hich enrolled 4,010 patients undergoing coronary angioplasty. The comb ination of a bolus plus either of 2 infusion doses of eptifibatide red uced the incidence of ischemic complications without increasing the ri sk of bleeding or other complications. Recent pharmacodynamic studies have established that more aggressive dosing of eptifibatide provides greater inhibition of ex vivo platelet aggregation and more robust ant ithrombotic activity. Higher doses of eptifibatide were therefore sele cted for the Platelet GP IIb-IIIa in Unstable Angina: Receptor Suppres sion Using Integrilin Therapy (PURSUIT) trial, which enrolled patients with unstable angina or non-Q-wave myocardial infarction. The availab le data suggest that eptifibatide may represent a useful clinical alte rnative to existing antiplatelet therapies. (C) 1997 by Excerpta Medic o, Inc.