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

This study describes the dose-exploration phase of the PRIDE trial, an inve stigation of the clinical pharmacology of higher dose eptifibatide in patie nts who underwent elective percutaneous coronary intervention (PCI). Outcom es of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dep endent upon proper dosing selection. In this multicenter, placebo-controlle d clinical study, 127 patients were randomized 1:1:2:2 into 1 of the follow ing treatment groups: placebo; eptifibatide as a 135 mug/kg bolus followed by a 0.75 mug/kg/min infusion; eptifibatide as a 180 mug/kg bolus with a 2. 0 mug/kg/min infusion; or eptifibatide as a 250 mug/kg bolus with a 3.0 mug /kg/min infusion. Light transmission aggregometry was used to determine pla telet aggregation in response to 20 muM adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear phar macokinetics over the dose range studied. Inhibition of platelet aggregatio n was greater in samples collected in sodium citrate compared with those co llected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone. The 180/ 2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediat ely (5 minutes) and at steady state (8 to 24 hours). At 1hour, mean inhibit ion of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 mu g/kg bolus followed by a 2.0 mug/kg/min infusion at steady state achieved > 80% inhibition of platelet aggregation. With the single-bolus regimen, howe ver, there was an early loss of the inhibition of platelet aggregation befo re steady state was reached. Additional dose-exploration studies may furthe r optimize eptifibatide dosing. (C) by Excerpta Medica, Inc.