title: Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention.
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.
  
  
  RESULTS
  Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/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-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/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.
authors.affiliation: Pennsylvania State University, Hershey, PA, USA. icg1@psu.edu
authors.forename: I C
authors.initials: IC
authors.lastname: Gilchrist
authors.forename: J C
authors.initials: JC
authors.lastname: O'Shea
authors.forename: T
authors.initials: T
authors.lastname: Kosoglou
authors.forename: L K
authors.initials: LK
authors.lastname: Jennings
authors.forename: T J
authors.initials: TJ
authors.lastname: Lorenz
authors.forename: M M
authors.initials: MM
authors.lastname: Kitt
authors.forename: N S
authors.initials: NS
authors.lastname: Kleiman
authors.forename: D
authors.initials: D
authors.lastname: Talley
authors.forename: F
authors.initials: F
authors.lastname: Aguirre
authors.forename: C
authors.initials: C
authors.lastname: Davidson
authors.forename: J
authors.initials: J
authors.lastname: Runyon
authors.forename: J E
authors.initials: JE
authors.lastname: Tcheng
mesh_terms: D015906:Angioplasty, Balloon, Coronary; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D000077542:Eptifibatide; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010455:Peptides / Q000493:pharmacokinetics*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D013997:Time Factors
chemical_list: D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000077542:Eptifibatide