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. Methods and Results-Patients (nϭ39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-g/kg bolus followed by 2 g/kg per minute or 250-g/kg bolus followed by 3 g/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 g/kg or 125 g/kg for the initial 180-g/kg or 250-g/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 Ͼ80% 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-g/kg bolus and a 2-g/kg per minute infusion followed by a second 180-g/kg bolus 10 minutes later. Conclusions-

Randomized COMparison of Platelet Inhibition With Abciximab, TiRofiban and Eptifibatide During Percutaneous Coronary Intervention in Acute Coronary Syndromes

“…Tirofiban dosing has been on the basis of inhibiting PA in response to a weak agonist (5 mol/L ADP), whereas current eptifibatide and abciximab regimens have been dosed to inhibit PA in response to more potent agonists (20 mol/L ADP and thrombin). [7][8][9][10] The use of citrated blood in determining tirofiban dosing may have also resulted in under-dosing relative to eptifibatide and abciximab, as our results and others 18 suggest that the calcium-chelating effects of citrate exaggerate ex vivo platelet inhibition with small molecule, low-affinity GP IIb/IIIa antagonists (eptifibatide and tirofiban). Unlike tirofiban, current eptifibatide regimens have already accounted for this phenomenon.…”

β2-Integrins and Acquired Glycoprotein IIb/IIIa (GPIIb/IIIa) Receptors Cooperate in NF-κB Activation of Human Neutrophils

“…We used abciximab at final concentrations of 100 ng/ml, eptifibatide at 1500 ng/ml, and tirofiban at 40 ng/ml. These concentrations are at the lower range of the in vivo levels found with treatment (12)(13)(14).…”

2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention

“…584,587-589,613-618,620 -626 Thus, recommendations about use of GP IIb/IIIa inhibitors are best construed as applying to those patients not at high risk of bleeding complications. Abciximab, double-bolus eptifibatide (180 mcg/kg bolus followed 10 minutes later by a second 180 mcg/kg bolus), and high-bolus dose tirofiban (25 mcg/kg) all result in a high degree of platelet inhibition, [627][628][629] have been demonstrated to reduce ischemic complications in patients undergoing PCI, 608,609,613,615,618 -621 and appear to lead to comparable angiographic and clinical outcomes. 630,631 Trials of GP IIb/IIIa inhibitors in the setting of STEMI and primary PCI were conducted in the era before routine stenting and DAPT.…”