Eptifibatide

also known as: Integrilin, Barbourin analog

Integrilin — the cyclic KGD-peptide GPIIb/IIIa inhibitor from pygmy rattlesnake venom. FDA-approved May 1998 (COR Therapeutics / Millennium Pharmaceuticals; now Merck / Viatris); reversible binding and short half-life make it tactically different from the monoclonal abciximab. One of two peptide-class GPIIb/IIIa antagonists in clinical use (the other being the non-peptide tirofiban).

A synthetic cyclic heptapeptide engineered from the disintegrin protein barbourin (from the venom of the southeastern pygmy rattlesnake, Sistrurus miliarius barbouri) by retaining the KGD (Lys-Gly-Asp) motif that confers selective fibrinogen binding to the platelet GPIIb/IIIa receptor. The peptide contains six amino acids plus a mercaptopropionyl (des-amino cysteinyl) group; a disulfide bridge between the terminal cysteine amide and the mercaptopropionyl forms the cyclic structure. FDA-approved May 18, 1998 (Integrilin®, COR Therapeutics / Key Pharmaceuticals, later Millennium Pharmaceuticals / Schering-Plough / Merck; generic availability post-2014) for acute coronary syndromes and percutaneous coronary intervention. Pivotal trials: PURSUIT (NEJM 1998) for unstable angina / non-ST-elevation MI; IMPACT-II (Lancet 1997) and ESPRIT for PCI.

Mechanism of action

Reversible, high-affinity antagonist at the platelet glycoprotein IIb/IIIa receptor (integrin αIIbβ3) — the final common pathway for platelet aggregation. The KGD motif within the cyclic heptapeptide structure mimics the RGD recognition sequence of fibrinogen (and vWF and fibronectin) and competitively blocks ligand binding to GPIIb/IIIa. Without GPIIb/IIIa / fibrinogen engagement, platelets cannot cross-link into aggregates regardless of upstream activation signals. Selectivity for αIIbβ3 over other integrins (αvβ3 and others) is conferred by the KGD specificity (versus RGD) — a feature of the parent barbourin peptide. Reversible binding with short plasma half-life means rapid offset after discontinuation (4–8 hours for platelet aggregation to normalise). No immunogenicity (unlike abciximab, which is a chimeric monoclonal antibody fragment and can produce HACA responses).

Primary uses

Acute coronary syndrome — unstable angina / non-ST-elevation myocardial infarction (FDA-approved)
Patients undergoing percutaneous coronary intervention including stent placement (FDA-approved)

Typical dosing

180 mcg/kg IV bolus followed by 2 mcg/kg/min infusion (PCI) or 180 mcg/kg bolus + 2 mcg/kg/min infusion continued up to 72 hours (ACS) mcg/kg and mcg/kg/min bolus + continuous infusion for procedure or admission duration (intravenous)

Dose reduction required in renal impairment (CrCl <50 mL/min: infusion reduced to 1 mcg/kg/min). Contraindicated in patients on dialysis, with active bleeding, recent stroke (<30 days), severe hypertension, or thrombocytopenia. Platelet transfusion does NOT reverse effect (reversible binding).

Regulatory status

FDA-approved May 18, 1998 (Integrilin®, COR Therapeutics / Key Pharmaceuticals). NDA 20-718. Indications: (1) treatment of patients with acute coronary syndrome (unstable angina / non-ST-segment-elevation MI) including those managed medically and those undergoing PCI; (2) patients undergoing PCI including those with intracoronary stenting. Acquired by Millennium Pharmaceuticals, later part of Schering-Plough and Merck (post-2009). Generic availability since 2014.

References

[fda-pi] Integrilin® (eptifibatide) Injection Prescribing Information. Merck / Millennium Pharmaceuticals. Initial US approval May 18, 1998.
[clinical-trial] PURSUIT Trial Investigators. "Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes." N Engl J Med, 1998;339(7):436-443.
[clinical-trial] IMPACT-II Investigators. "Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention (IMPACT-II)." Lancet, 1997;349(9063):1422-1428.

Related peptides

Bivalirudin

Angiomax — the workhorse direct thrombin inhibitor for percutaneous coronary intervention. FDA-approved December 2000 (The Medicines Company, now Sandoz); the first synthetic peptide DTI to achieve broad PCI adoption. REPLACE-2, ACUITY, and HORIZONS-AMI trials established the anticoagulant profile; subsequent MATRIX trial outcomes shifted practice in some populations back toward heparin.

Quick facts

Class

A cyclic heptapeptide (6 amino acids plus a mercaptopropionyl residue, closed by a disulfide bridge) rationally designed from barbourin — a disintegrin peptide found in the venom of the southeastern pygmy rattlesnake (Sistrurus miliarius barbouri) — that reversibly inhibits fibrinogen binding to the platelet GPIIb/IIIa receptor.

Subcategory

Platelet glycoprotein IIb/IIIa receptor antagonist (cyclic peptide)

Sequence

Mpa-Har-Gly-Asp-Trp-Pro-Cys-NH2 (cyclic via Mpa-Cys disulfide; Mpa = mercaptopropionyl; Har = homoarginine)

Molecular formula

C35H49N11O9S2

Molecular weight

831.96 Da

Half-life

2–3 hours — Renally cleared (~50%); half-life extended in renal impairment. Platelet aggregation returns to normal 4–8 hours after discontinuation, making it the shortest-acting GPIIb/IIIa inhibitor. Reversibility of binding means platelet transfusion does not reverse the effect.

Evidence level

High

Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.