Platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention: focus on the pharmacokinetic-pharmacodynamic relationships of eptifibatide.

Eptifibatide is a truncated derivative of the naturally occurring rattlesnake venom protein known as barbourin. It is a cyclic heptapeptide that mimics the tertiary structure found in the parent compound which allows it to bind receptors with the KGD (Lys-Gly-Asp) peptide recognition sequence. Specifically, eptifibatide is a competitive antagonist for the activated platelet glycoprotein IIb/IIIa receptor. Its mechanism of action involves preventing the binding and cross-linking of fibrinogen to the platelet surface. This binding site for fibrinogen is associated with five Ca2+ ions that help maintain the tertiary structure of the receptor and affect the affinity of other ligands such as eptifibatide. Arterial injury induced by percutaneous coronary interventions (PCI) such as balloon angioplasty and stenting, and the spontaneously occurring disease process known as the acute coronary syndrome (ACS), share a common underlying pathophysiology. In both situations, disruption of integrity of the arterial wall initiates a cascade of platelet activation, adhesion and aggregation. Ultimately, this process may proceed to arterial thrombosis unless controlled or modified. Advances in understanding how the platelet plays a pivotal role in this process have significantly enhanced therapy for patients with ACS and have resulted in important reductions in thrombotic complications from PCI procedures. Central to these advances has been evolving understanding of platelet-inhibiting pharmaceutical agents such as eptifibatide. The development of a rational administration regimen for eptifibatide parallels the growth in the understanding of the underlying mechanisms of platelet receptor functions. The binding of eptifibatide to the receptor involves displacement of receptor-associated Ca2+ from the activated binding site. Early in the clinical development of eptifibatide, this was poorly appreciated and resulted in an underestimation of the appropriate doses for this agent. Through a series of small clinical trials and laboratory studies, deficiencies in the early administration regimens were identified and a more effective dose schedule was determined. Modelling of the drug based on its two-compartment pharmacokinetics further defined the role of a newer double-bolus initiation of therapy verses the original single-bolus approach. In a large-scale clinical trial using this double-bolus followed by infusion regimen in PCI procedures, clinical efficacy was shown to be significantly improved over placebo and the earlier, low-dose regimens used in the original trials of eptifibatide.