Elsevier

American Heart Journal

Volume 138, Issue 6, December 1999, Pages 1093-1104
American Heart Journal

Development of eptifibatide,☆☆,

https://doi.org/10.1016/S0002-8703(99)70075-XGet rights and content

Abstract

Background The primary cause of acute coronary syndromes is the development of a thrombus, a pathologic manifestation of platelet aggregation that occurs as part of the normal process of hemostasis. The discovery that the final common step in platelet aggregation, through the binding of fibrinogen to the activated platelet integrin glycoprotein (GP) IIb/IIIa, has opened the door to the development of novel and potentially more effective antithrombotic therapies. Abciximab, a human-murine chimeric Fab fragment of a monoclonal antibody against the GP IIb/IIIa receptor, was the first agent of this class to demonstrate clinical effectiveness. Several of the specific properties of abciximab, such as its long half-life, lack of receptor-blocking specificity, and some tendency for antigenicity, have prompted the development of alternative GP IIb/IIIa inhibitors with distinct pharmacologic profiles. Methods and Results One of these newer agents is eptifibatide, which was developed by mimicking the GP IIb/IIIa blocker barbourin, found in the venom of the southeastern pigmy rattlesnake. Eptifibatide is a small, cyclic heptapeptide that has shown high specificity and high affinity for GP IIb-IIIa, a short plasma half-life, and rapid onset of antiplatelet action accompanied by a rapid reversibility of platelet inhibition once treatment is stopped. Conclusions In clinical trials, culminating in the phase III IMPACT II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis) and PURSUIT (Platelet GP IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trials, eptifibatide was found to reduce coronary events significantly in a broad range of low-, medium-, and high-risk patients with acute coronary syndromes without significantly increasing the risk of bleeding or other complications. These results suggest that eptifibatide may prove to be an effective addition to currently available antithrombotic therapies. (Am Heart J 1999;138:1093-104.)

Section snippets

Development of inhibitors of the platelet receptor GP IIb/IIIa

The first GP IIb/IIIa inhibitor to be tested in clinical trials was a Fab fragment of an anti-GP IIb/IIIa murine monoclonal antibody, m7E3.10 Several small clinical trials demonstrated that m7E3 Fab can effectively block GP IIb/IIIa in human beings. It was evident from these studies that several potential safety concerns might be associated with this pharmacologic approach.11, 12 Low titers of anti-m7E3 serum antibodies were detected in a number of healthy individuals and patients with stable

Synthesis of eptifibatide

During the past decade, a wide range of snake viper venoms have been shown to contain a family of compounds called disintegrins, small proteins that act as powerful antithrombotics and strongly inhibit platelet aggregation.22, 23 Almost all these small proteins contain the amino acid sequence RGD (Arg-Gly-Asp), which is believed to play a role in the binding of fibrinogen to GP IIb/IIIa. However, RGD-containing venom disintegrins also bind to a number of other integrins, such as α5β1

Pharmacology of eptifibatide

Eptifibatide, like other antagonists of platelet receptor GP IIb/IIIa, functions by blocking the binding of the adhesive proteins fibrinogen and von Willebrand factor to GP IIb/IIIa on the surface of activated platelets. It is a potent antithrombotic because the binding of these proteins to GP IIb/IIIa is the event that precipitates platelet aggregation and subsequent arterial thrombus formation. As a critical prelude to clinical trials, studies were undertaken to determine the relation between

Antiplatelet activity of eptifibatide

Determination of an ex vivo surrogate to predict in vivo activity of eptifibatide has relied primarily on its effects in an ex vivo platelet aggregation assay. In all early clinical studies, this assay was routinely performed in blood anticoagulated with citrate. Citrate prevents in vitro clotting of blood samples by reducing the ionized calcium concentration from the 1.1 mmol/L normally found in circulating blood to 40 to 50 μmol/L. Therefore ionized calcium concentration has been

Pharmacodynamics of eptifibatide in animal models

Several preclinical experiments to test the efficacy and safety of eptifibatide in nonhuman species produced promising results. An animal study with a canine model to investigate the effects of eptifibatide on fibrinogen-triggered platelet adhesion and postoperative bleeding related to cardiopulmonary bypass found a rapidly reversible antihemostatic effect of eptifibatide, which was associated with seemingly paradoxic minimization of postoperative bleeding. The reduction of postoperative

Studies in healthy volunteers

A potent and rapidly reversible inhibition of GP IIb/IIIa by eptifibatide was demonstrated in healthy volunteers in a variety of clinical settings. For infusions ranging from 0.2 to 1.5 μg/kg/min, plasma concentrations of eptifibatide were proportional to the dose and rate of eptifibatide administration. In these studies, the plasma elimination half-life of eptifibatide was 50 to 60 minutes. In a phase I investigation of 63 healthy volunteers, ADP-stimulated platelet aggregation was completely

The IMPACT-II trial

IMPACT II was a randomized, double-blind, placebo-controlled phase III clinical trial designed to investigate the efficacy of eptifibatide in reducing ischemic complications of percutaneous coronary revascularization in a broad range of patients.37 The study was performed in 84 centers in the United States between November 1993 and November 1994 and involved 4010 patients scheduled for either elective, urgent, or emergency coronary intervention (balloon angioplasty, directional coronary

Summary

There are several physiologic cascades that ultimately lead to the aggregation of platelets and thrombosis, but all converge on the platelet receptor GP IIb/IIIa. The interaction of activated GP IIb/IIIa with its ligands represents the final common pathway for platelet aggregation. For this reason, a GP IIb/IIIa blockade has promise as an almost ideal antithrombotic therapy, overcoming the limitations of traditional antithrombotic therapies. Because GP IIb/IIIa is found only on platelets and

References (41)

  • BS Coller

    Platelets in cardiovascular thrombosis and thrombolysis

  • S Coute et al.

    Novel antithrombotic therapeutics targeted against platelet glycoprotein IIb/IIIa

    Ann Rev Med

    (1995)
  • K Gotoh et al.

    The role of intracoronary thrombus in unstable angina: angiographic assessment and thrombolytic therapy during ongoing anginal attacts

    Circulation

    (1988)
  • MJ Davies

    A macro and micro view of coronary vascular insult in ischemic heart disease

    Circulation

    (1990)
  • MA DeWood et al.

    Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction

    N Engl J Med

    (1980)
  • C Landau et al.

    Percutaneous transluminal coronary angioplasty

    N Engl J Med

    (1994)
  • JM Wilson et al.

    Abrupt vascular closure

    J Invas Cardiol

    (1994)
  • BS Coller et al.

    Glanzmann thrombasthenia: new insights from an historical perspective

    Semin Hematol

    (1994)
  • RE Jordan et al.

    Pharmacology and clinical development of abciximab (c7E3 Fab, ReoPro): a monoclonal antibody inhibitor of GPIIb/IIIa and αvβ3

  • SG Ellis et al.

    Safety and antiplatelet effect of murine monoclonal antibody 7E3 Fab directed against platelet glycoprotein IIb/IIIa in patients undergoing elective coronary angioplasty

    Coron Art Dis

    (1993)
  • Cited by (134)

    • Future perspectives on peptide therapeutics

      2022, Peptide and Peptidomimetic Therapeutics: From Bench to Bedside
    • Toxinology provides multidirectional and multidimensional opportunities: A personal perspective

      2020, Toxicon: X
      Citation Excerpt :

      This changed the paradigm from “toxin as a villain” to “toxin as a savior”. Similarly, discovery of disintegrins from Trimeresurus gramineus (Indian green pit viper) and Echis carinatus (saw scaled viper) venoms (Huang et al., 1987, 1989; Gan et al., 1988) culminated in the development of potent antiplatelet agents, eptifibatide (Scarborough et al., 1993; Phillips and Scarborough, 1997; Scarborough, 1999) and tirofiban (Barrett et al., 1994; Lynch et al., 1995). Vipegitide, a folded peptidomimetic is being developed as partial antagonist of α2β1 integrin and an antithrombotic agent based on a snaclec from Vipera palaestinae venom (Arlinghaus et al., 2013; Momic et al., 2015).

    • Detection and identification of antibacterial proteins in snake venoms using at-line nanofractionation coupled to LC-MS

      2018, Toxicon
      Citation Excerpt :

      Many academic groups have put significant efforts into studying snake venoms and understanding their biological effects. Moreover, snake venoms have traditionally served as an important source of compounds in drug discovery (Cook et al., 1999; King, 2011; Ryan J. R. McCleary, 2015; Scarborough, 1999; Smith and Vane, 2003). On the antibacterial properties of both crude snake venoms and compounds purified from snake venoms, many studies have been conducted.

    View all citing articles on Scopus

    Guest Editor for this manuscript was David P. Faxon, MD, University of Southern California School of Medicine, Los Angeles.

    ☆☆

    Reprint requests: Robert M. Scarborough, PhD, COR Therapeutics, Inc, 256 E Grand Ave, South San Francisco, CA 94080.

    0002-8703/99/$8.00 + 0   4/1/96757

    View full text