Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention

Background-Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagoni st of platelet glycoprotein IIb/IIIa, are substantially altered by anticoag ulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characteri ze the pharmacodynamics and pharmacokinetics of eptifibatide under physiolo gical conditions. Methods and Results-Patients (n=39) undergoing elective percutaneous corona ry intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-mug/kg bolus followed by 2 mug/kg per minute or 250-mug/k g bolus followed by 3 mug/kg per minute) for 18 to 24 hours. In a 2:1 ratio , these patients received either a second bolus of eptifibatide (90 mug/kg or 125 mug/kg for the initial 180-mug/kg or 250-mug/kg groups, respectively ) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo pl atelet aggregation, receptor occupancy, and plasma eptifibatide levels at b aseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibiti on was dose dependent and >80% in all groups by steady state. The single-bo lus regimens had a transient loss of inhibition at I hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-mug/kg bo lus and a 2-mug/kg per minute infusion followed by a second 180-mug/kg bolu s 10 minutes later. Conclusions-A novel higher-dose, double-bolus regimen of eptifibatide in co ronary intervention attains and maintains >90% inhibition of platelet aggre gation in >90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary st ent implantation.