Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study)

Abstract

This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 μg/kg bolus followed by a 0.75 μg/kg/min infusion; eptifibatide as a 180 μg/kg bolus with a 2.0 μg/kg/min infusion; or eptifibatide as a 250 μg/kg bolus with a 3.0 μg/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 μM adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in d-phenylalanyl- l-prolyl- l-arginine chloromethyl ketone. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8 to 24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 μg/kg bolus followed by a 2.0 μg/kg/min infusion at steady state achieved >80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing.