Eptifibatide

Eptifibatide, a synthetic cyclic heptapeptide containing six amino acids, including one cysteine amide and one mercaptopropionyl (desamino cysteinyl) residue, is an inhibitor of platelet aggregation and belongs to the class of RGD (arginine-glycine-aspartate)-mimetics.

Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor and other adhesive ligands to the glycoprotein (GP) IIb/IIIa receptors.

Pharmacodynamic effects

Eptifibatide inhibits platelet aggregation in a dose- and concentration-dependent manner as demonstrated by ex vivo platelet aggregation using adenosine diphosphate (ADP) and other agonists to induce platelet aggregation. The effect of eptifibatide is observed immediately after administration of a 180 microgram/kg intravenous bolus. When followed by a 2.0 microgram/kg/min continuous infusion, this regimen produces a >80% inhibition of ADP-induced ex vivo platelet aggregation, at physiologic calcium concentrations, in more than 80% of patients.

Platelet inhibition was readily reversed, with a return of platelet function towards baseline (>50% platelet aggregation) 4 hours after stopping a continuous infusion of 2.0 microgram/kg/min. Measurements of ADP-induced ex vivo platelet aggregation at physiologic calcium concentrations (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone anticoagulant) in patients presenting with unstable angina and Non Q-Wave Myocardial Infarction showed a concentration-dependent inhibition with an IC₅₀ (50% inhibitory concentration) of approximately 550 ng/ml and an IC₈₀ (80% inhibitory concentration) of approximately 1,100 ng/ml.

There is limited data with regards to platelet inhibition in patients with renal impairment. In patients with moderate renal impairment, (creatinine clearance 30–50mL/min) 100% inhibition was achieved at 24 hours following administration of 2 microgram/kg/min. In patients with severe renal impairment (creatinine clearance <30mL/min) administered 1microgram/kg/min, 80% inhibition was achieved in more than 80% of patients at 24 hours.

The pharmacokinetics of eptifibatide are linear and dose proportional for bolus doses ranging from 90 to 250 microgram/kg and infusion rates from 0.5 to 3.0 microgram/kg/min. For a 2.0 microgram/kg/min infusion, mean steady-state plasma eptifibatide concentrations range from 1.5 to 2.2 microgram/ml in patients with coronary artery disease. These plasma concentrations are achieved rapidly when the infusion is preceded by a 180 microgram/kg bolus. The extent of eptifibatide binding to human plasma protein is about 25%. In the same population, plasma elimination half-life is approximately 2.5 hours, plasma clearance 55 to 80 ml/kg/hr and volume of distribution of approximately 185 to 260 ml/kg.

In healthy subjects, renal excretion accounted for approximately 50% of total body clearance; approximately 50% of the amount cleared is excreted unchanged. In patients with moderate to severe renal insufficiency (creatinine clearance <50 ml/min), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels are approximately doubled.

No formal pharmacokinetic interaction studies have been conducted. However, in a population pharmacokinetic study there was no evidence of a pharmacokinetic interaction between eptifibatide and the following concomitant medicinal products: amlodipine, atenolol, atropine, captopril, cefazolin, diazepam, digoxin, diltiazem, diphenhydramine, enalapril, fentanyl, furosemide, heparin, lidocaine, lisinopril, metoprolol, midazolam, morphine, nitrates, nifedipine, and warfarin.

Toxicology studies conducted with eptifibatide include single and repeated dose studies in the rat, rabbit and monkey, reproduction studies in the rat and rabbit, in vitro and in vivo genetic toxicity studies, and irritation, hypersensitivity and antigenicity studies. No unexpected toxic effects for an agent with this pharmacologic profile were observed and findings were predictive of clinical experience, with bleeding effects being the principal adverse event. No genotoxic effects were observed with eptifibatide.

Teratology studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis) and in pregnant rabbits at total daily doses of up to 36 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis). These studies revealed no evidence of impaired fertility or harm to the foetus due to eptifibatide. Reproduction studies in animal species where eptifibatide shows a similar pharmacologic activity as in humans are not available. Consequently these studies are not suitable to evaluate the toxicity of eptifibatide on reproductive function.

The carcinogenic potential of eptifibatide has not been evaluated in long-term studies.