Clinical Pharmacology of Eptifibatide

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Abstract

Activation of receptor function of platelet membrane glycoprotein (GP) IIb-IIIa leads to the binding of fibrinogen and is the final common pathway to platelet aggregation. Platelet aggregates provide the structural basis for coronary thrombosis, a major cause of ischemic heart disease. GP IIb-IIIa has a narrow tissue distribution, being found only on platelets and their progenitors, and inhibition of its receptor function has emerged as a promising new therapeutic strategy for management of acute ischemic coronary syndromes and acute ischemic complications of percutaneous coronary interventions. Eptifibatide (INTEGRILIN) is a cyclic heptapeptide inhibitor of GP IIb-IIIa, with an active pharmacophore that is derived from the structure of barbourin, a GP IIb-IIIa 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 pharmacologic studies have established that eptifibatide can inhibit thrombosis effectively, with only modest effects on bleeding time measurements. Pharmacokinetic and pharmacodynamic studies in both animal models and humans have shown that the antiplatelet effect of eptifibatide has a rapid onset of action and that the drug has a short plasma half-life. Furthermore, the rapid reversibility of action of eptifibatide, exemplified by an antihemostatic effect limited to the period of drug administration, was apparent in both healthy volunteers and patients with ischemic heart disease. In clinical trials, eptifibatide has not been found to be immunogenic or to induce thrombocytopenia. These studies have led to the evaluation of eptifibatide in the pivotal Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT II) trial, which enrolled 4,010 patients undergoing coronary angioplasty. The combination of a bolus plus either of 2 infusion doses of eptifibatide reduced the incidence of ischemic complications without increasing the risk 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 antithrombotic activity. Higher doses of eptifibatide were therefore selected for the Platelet GP IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, which enrolled patients with unstable angina or non-Q-wave myocardial infarction. The available data suggest that eptifibatide may represent a useful clinical alternative to existing antiplatelet therapies.

Section snippets

Platelet Membrane GP IIb-IIIa Complex

GP IIb-IIIa belongs to a large family of receptors called integrins, which are heterodimeric cell-surface proteins that play important roles in cell adhesions.14, 21, 22, 23Unlike most integrins, GP IIb-IIIa has a narrow tissue distribution, being found only on platelets and cells of the megakaryocytic lineage. GP IIb-IIIa is the most abundant protein on the surface of platelets, with some 80,000 copies per platelet,[24]representing 1–2% of total platelet protein.[25]

As depicted in Fig. 1, GP

Development of GP IIb-IIIa Inhibitors

The first GP IIb-IIIa inhibitor to be developed and extensively evaluated clinically is abciximab (ReoPro, Centocor, Malvern, PA/Eli Lilly, Indianapolis, IN),[40]a human-murine chimeric monoclonal antibody fragment derived from the murine monoclonal antibody 7E3.[41]Abciximab is an effective blocker of GP IIb-IIIa receptor function and has demonstrated antithrombotic efficacy in advanced clinical trials.42, 43The pharmacologic profile of abciximab is reflective of its high affinity for GP

Pharmacodynamics and Pharmacokinetics of Eptifibatide

The main goal of pharmacodynamic and pharmacokinetic studies with eptifibatide has been to correlate the antiplatelet activity of eptifibatide (as measured by its ability to inhibit platelet aggregation and thrombosis) with its plasma levels. On the basis of these studies, several dosing regimens of eptifibatide have been selected, and their effect on bleeding times has been measured in order to evaluate the safety profile of this drug.

Dose Selection of Eptifibatide in the Impact II and PURSUIT Trials

The dosing regimens of eptifibatide in the pivotal IMPACT II trial were selected to achieve effective antithrombotic activity safely during the procedure and in the critical hours after PTCA. IMPACT II randomized 4,010 low- and high-risk patients scheduled to undergo percutaneous intervention to receive either a placebo or 1 of the 2 eptifibatide doses.[20]All patients in the eptifibatide arms received the same 135-μg/kg bolus, which was selected because it provided a robust and rapid

Conclusions and Prospects

The conventional approaches to the management of coronary thrombosis underlying AICS and the ischemic complications of percutaneous coronary interventions have been anticoagulation with heparin and antiplatelet therapy with aspirin. The efficacy of each of these agents, however, is limited by their relatively weak effect on platelet aggregation, a key event in the pathophysiology of ischemic heart disease. The platelet GP IIb-IIIa complex involved in the final common pathway to platelet

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