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 |
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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 |
format | Article |
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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.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/hc2901.093504</identifier><identifier>PMID: 11468201</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>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</subject><ispartof>Circulation (New York, N.Y.), 2001-07, Vol.104 (4), p.406-411</ispartof><rights>2001 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. Jul 24, 2001</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c425t-89925665d3bc8e195596c28f05a44fe8452400b7afa0e0a88780a8439a034eb3</citedby><cites>FETCH-LOGICAL-c425t-89925665d3bc8e195596c28f05a44fe8452400b7afa0e0a88780a8439a034eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,3689,27931,27932</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1093136$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11468201$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GILCHRIST, Ian C</creatorcontrib><creatorcontrib>O'SHEA, J. 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. 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.</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. Drug treatments</subject><subject>Platelet Aggregation - drug effects</subject><subject>Platelet Aggregation Inhibitors - pharmacokinetics</subject><subject>Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors</subject><subject>Time Factors</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1L5jAQxoMo-uruca9SRDxZd_LVNkcRPxYE9-C9pOl032ib1KRdeP97Iy0oXmaYmR8PM_MQ8ovCFaUF_b01TAG9AsUliD2yoZKJXEiu9skGAFRecsaOyHGML6kseCkPyRGloqgY0A2Z_251GLTx7c7pwZqYaddm49p8tQ6nj6bvsq39t8WQtz7iZdb6uekxb3w_xwzHyXa20ZNtMbMuGzGYedIOfRoaH7zTYZcGE4b_6Cbr3Q9y0Ok-4s81n5Dnu9vnm4f88en-z831Y24Ek1NeKcVkUciWN6ZCqqRUhWFVB1IL0WEl0q0ATak7DQi6qsoqRcGVBi6w4SfkYpEdg3-bMU71YKPBvl92q0sKTBVcJvDsG_ji5-DSajWjrARRCpagfIFM8DEG7Oox2CGdVlOoP7yoFy_qxYvEn66iczNg-0mvz0_A-QroaHTfBe2MjV9UFae84O_Az5I0</recordid><startdate>20010724</startdate><enddate>20010724</enddate><creator>GILCHRIST, Ian C</creator><creator>O'SHEA, J. Conor</creator><creator>RUNYON, John</creator><creator>TCHENG, James E</creator><creator>KOSOGLOU, Teddy</creator><creator>JENNINGS, Lisa K</creator><creator>LORENZ, Todd J</creator><creator>KITT, Michael M</creator><creator>KLEIMAN, Neal S</creator><creator>TALLEY, David</creator><creator>AGUIRRE, Frank</creator><creator>DAVIDSON, Charles</creator><general>Lippincott Williams & Wilkins</general><general>American Heart Association, Inc</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>U9A</scope><scope>7X8</scope></search><sort><creationdate>20010724</creationdate><title>Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c425t-89925665d3bc8e195596c28f05a44fe8452400b7afa0e0a88780a8439a034eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Angioplasty, Balloon, Coronary</topic><topic>Area Under Curve</topic><topic>Biological and medical sciences</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Dose-Response Relationship, Drug</topic><topic>Eptifibatide</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic Clearance Rate</topic><topic>Middle Aged</topic><topic>Peptides - pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Platelet Aggregation - drug effects</topic><topic>Platelet Aggregation Inhibitors - pharmacokinetics</topic><topic>Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GILCHRIST, Ian C</creatorcontrib><creatorcontrib>O'SHEA, J. 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><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GILCHRIST, Ian C</au><au>O'SHEA, J. 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 >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.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & 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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