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

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 phar...

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Veröffentlicht in:Circulation (New York, N.Y.) N.Y.), 2001-07, Vol.104 (4), p.406-411
Hauptverfasser: GILCHRIST, Ian C, O'SHEA, J. Conor, RUNYON, John, TCHENG, James E, KOSOGLOU, Teddy, JENNINGS, Lisa K, LORENZ, Todd J, KITT, Michael M, KLEIMAN, Neal S, TALLEY, David, AGUIRRE, Frank, DAVIDSON, Charles
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container_end_page 411
container_issue 4
container_start_page 406
container_title Circulation (New York, N.Y.)
container_volume 104
creator GILCHRIST, Ian C
O'SHEA, J. Conor
RUNYON, John
TCHENG, James E
KOSOGLOU, Teddy
JENNINGS, Lisa K
LORENZ, Todd J
KITT, Michael M
KLEIMAN, Neal S
TALLEY, David
AGUIRRE, Frank
DAVIDSON, Charles
description 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. 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. 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.
doi_str_mv 10.1161/hc2901.093504
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Conor</creatorcontrib><creatorcontrib>RUNYON, John</creatorcontrib><creatorcontrib>TCHENG, James E</creatorcontrib><creatorcontrib>KOSOGLOU, Teddy</creatorcontrib><creatorcontrib>JENNINGS, Lisa K</creatorcontrib><creatorcontrib>LORENZ, Todd J</creatorcontrib><creatorcontrib>KITT, Michael M</creatorcontrib><creatorcontrib>KLEIMAN, Neal S</creatorcontrib><creatorcontrib>TALLEY, David</creatorcontrib><creatorcontrib>AGUIRRE, Frank</creatorcontrib><creatorcontrib>DAVIDSON, Charles</creatorcontrib><title>Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>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. 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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. A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains &gt;90% inhibition of platelet aggregation in &gt;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.</description><subject>Angioplasty, Balloon, Coronary</subject><subject>Area Under Curve</subject><subject>Biological and medical sciences</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Dose-Response Relationship, Drug</subject><subject>Eptifibatide</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic Clearance Rate</subject><subject>Middle Aged</subject><subject>Peptides - pharmacokinetics</subject><subject>Pharmacology. 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Conor</au><au>RUNYON, John</au><au>TCHENG, James E</au><au>KOSOGLOU, Teddy</au><au>JENNINGS, Lisa K</au><au>LORENZ, Todd J</au><au>KITT, Michael M</au><au>KLEIMAN, Neal S</au><au>TALLEY, David</au><au>AGUIRRE, Frank</au><au>DAVIDSON, Charles</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2001-07-24</date><risdate>2001</risdate><volume>104</volume><issue>4</issue><spage>406</spage><epage>411</epage><pages>406-411</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>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. 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 &gt;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. A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains &gt;90% inhibition of platelet aggregation in &gt;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.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams &amp; Wilkins</pub><pmid>11468201</pmid><doi>10.1161/hc2901.093504</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
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subjects Angioplasty, Balloon, Coronary
Area Under Curve
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Dose-Response Relationship, Drug
Eptifibatide
Female
Humans
Male
Medical sciences
Metabolic Clearance Rate
Middle Aged
Peptides - pharmacokinetics
Pharmacology. Drug treatments
Platelet Aggregation - drug effects
Platelet Aggregation Inhibitors - pharmacokinetics
Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors
Time Factors
title Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention
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