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(Circulation. 2001;104:406.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Pharmacodynamics and Pharmacokinetics of Higher-Dose, Double-Bolus Eptifibatide in Percutaneous Coronary Intervention

Ian C. Gilchrist, MD; J. Conor O’Shea, MD; Teddy Kosoglou, PharmD; Lisa K. Jennings, PhD; Todd J. Lorenz, MD; Michael M. Kitt, MD; Neal S. Kleiman, MD; David Talley, MD; Frank Aguirre, MD; Charles Davidson, MD; John Runyon, MD; James E. Tcheng, MD

From Pennsylvania State University, Hershey, Pa (I.C.G.); Duke Clinical Research Institute, Durham, NC (J.C.O., J.E.T.); Schering-Plough Research Institute, Kenilworth, NJ (T.K.); the University of Tennessee, Memphis (L.K.J.); COR Therapeutics, Inc, South San Francisco, Calif (T.J.L., M.M.K.); Baylor College of Medicine, Houston, Tex (N.S.K.); the University of Arkansas, Little Rock (D.T.); St Louis University Health Sciences Center, St Louis, Mo (F.A.); Northwestern University, Chicago, Ill (C.D.); and Christ Hospital, Cincinnati, Ohio (J.R.).

Correspondence to Ian C. Gilchrist, 500 University Dr, Room C1517, MS Hershey Medical Center, Hershey, PA 17033-0850. E-mail icg1{at}psu.edu

Background— Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions.

Methods and Results— Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-µg/kg bolus followed by 2 µg/kg per minute or 250-µg/kg bolus followed by 3 µg/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 µg/kg or 125 µg/kg for the initial 180-µg/kg or 250-µg/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and >80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-µg/kg bolus and a 2-µg/kg per minute infusion followed by a second 180-µg/kg bolus 10 minutes later.

Conclusions— A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains >90% inhibition of platelet aggregation 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 stent implantation.

Key Words: glycoproteins • stents • pharmacokinetics

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