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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)406-411
Number of pages6
JournalCirculation
Volume104
Issue number4
DOIs
StatePublished - Jul 24 2001

Keywords

  • Glycoproteins
  • Pharmacokinetics
  • Stents

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Gilchrist, I. C., O'Shea, J. C., Kosoglou, T., Jennings, L. K., Lorenz, T. J., Kitt, M. M., Kleiman, N. S., Talley, D., Aguirre, F., Davidson, C., Runyon, J., & Tcheng, J. E. (2001). Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention. Circulation, 104(4), 406-411. https://doi.org/10.1161/hc2901.093504