Population Pharmacodynamic Modelling of Aspirin- and Ibuprofen-Induced Inhibition of Platelet Aggregation in Healthy Subjects

Objective: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. Methods: Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way...

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Veröffentlicht in:Clinical pharmacokinetics 2008-01, Vol.47 (2), p.129-137
Hauptverfasser: Hong, Ying, Gengo, Fran M., Rainka, Michelle M., Bates, Vernice E., Mager, Donald E.
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container_end_page 137
container_issue 2
container_start_page 129
container_title Clinical pharmacokinetics
container_volume 47
creator Hong, Ying
Gengo, Fran M.
Rainka, Michelle M.
Bates, Vernice E.
Mager, Donald E.
description Objective: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. Methods: Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way crossover study. Treatments consisted of single doses of oral aspirin (325 mg) and ibuprofen (400 mg) and concomitant administration of aspirin (325 mg) and ibuprofen (400 mg). Ex vivo whole blood platelet aggregation induced by collagen (1 μg/mL) or arachidonic acid (0.5 mmol/L) was measured by impedance aggregometry. Model development and population parameter estimation were performed using nonlinear mixed-effects modelling implemented in NONMEM. Results: Relatively complete inhibition of platelet aggregation was achieved following aspirin treatment (∼77% inhibition within 2 hours), and return to baseline values occurred within 72–96 hours after dosing. In contrast, treatment with ibuprofen alone or in combination with aspirin produced transient inhibition of platelet aggregation, with complete recovery observed in 6–8 hours. The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (k out ) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h −1 and 0.152 (mg/L) −1 · h −1 , with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. Conclusions: A mechanism-based pharmacodynamic model has been developed that characterizes the anti-platelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.
doi_str_mv 10.2165/00003088-200847020-00006
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The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (k out ) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h −1 and 0.152 (mg/L) −1 · h −1 , with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. Conclusions: A mechanism-based pharmacodynamic model has been developed that characterizes the anti-platelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.</description><identifier>ISSN: 0312-5963</identifier><identifier>EISSN: 1179-1926</identifier><identifier>DOI: 10.2165/00003088-200847020-00006</identifier><identifier>PMID: 18193919</identifier><identifier>CODEN: CPKNDH</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Administration, Oral ; Adult ; Arachidonic Acid - pharmacology ; Aspirin - blood ; Aspirin - pharmacokinetics ; Aspirin - pharmacology ; Biological and medical sciences ; Blood. Blood coagulation. Reticuloendothelial system ; Collagen - pharmacology ; Cross-Over Studies ; Cyclooxygenase Inhibitors - administration &amp; dosage ; Cyclooxygenase Inhibitors - pharmacokinetics ; Cyclooxygenase Inhibitors - pharmacology ; Half-Life ; Humans ; Ibuprofen - blood ; Ibuprofen - pharmacokinetics ; Ibuprofen - pharmacology ; Internal Medicine ; Medical sciences ; Medicine ; Medicine &amp; Public Health ; Middle Aged ; Models, Biological ; Monte Carlo Method ; Original Research Article ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Pharmacotherapy ; Platelet Aggregation - drug effects ; Platelet Aggregation Inhibitors - administration &amp; dosage ; Platelet Aggregation Inhibitors - pharmacokinetics ; Platelet Aggregation Inhibitors - pharmacology ; Single-Blind Method ; Time Factors</subject><ispartof>Clinical pharmacokinetics, 2008-01, Vol.47 (2), p.129-137</ispartof><rights>Adis Data Information BV 2008</rights><rights>2008 INIST-CNRS</rights><rights>COPYRIGHT 2008 Wolters Kluwer Health, Inc.</rights><rights>Copyright Wolters Kluwer Health Adis International 2008</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c512t-24a684a6ce6fa0a981d06135188f1b77f789e003097d85b10fa8dbb632ca4b523</citedby><cites>FETCH-LOGICAL-c512t-24a684a6ce6fa0a981d06135188f1b77f789e003097d85b10fa8dbb632ca4b523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.2165/00003088-200847020-00006$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.2165/00003088-200847020-00006$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=20134124$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18193919$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hong, Ying</creatorcontrib><creatorcontrib>Gengo, Fran M.</creatorcontrib><creatorcontrib>Rainka, Michelle M.</creatorcontrib><creatorcontrib>Bates, Vernice E.</creatorcontrib><creatorcontrib>Mager, Donald E.</creatorcontrib><title>Population Pharmacodynamic Modelling of Aspirin- and Ibuprofen-Induced Inhibition of Platelet Aggregation in Healthy Subjects</title><title>Clinical pharmacokinetics</title><addtitle>Clin Pharmacokinet</addtitle><addtitle>Clin Pharmacokinet</addtitle><description>Objective: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. 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The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (k out ) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h −1 and 0.152 (mg/L) −1 · h −1 , with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. 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Reticuloendothelial system</subject><subject>Collagen - pharmacology</subject><subject>Cross-Over Studies</subject><subject>Cyclooxygenase Inhibitors - administration &amp; dosage</subject><subject>Cyclooxygenase Inhibitors - pharmacokinetics</subject><subject>Cyclooxygenase Inhibitors - pharmacology</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Ibuprofen - blood</subject><subject>Ibuprofen - pharmacokinetics</subject><subject>Ibuprofen - pharmacology</subject><subject>Internal Medicine</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine &amp; Public Health</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Monte Carlo Method</subject><subject>Original Research Article</subject><subject>Pharmacology. 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Blood coagulation. Reticuloendothelial system</topic><topic>Collagen - pharmacology</topic><topic>Cross-Over Studies</topic><topic>Cyclooxygenase Inhibitors - administration &amp; dosage</topic><topic>Cyclooxygenase Inhibitors - pharmacokinetics</topic><topic>Cyclooxygenase Inhibitors - pharmacology</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Ibuprofen - blood</topic><topic>Ibuprofen - pharmacokinetics</topic><topic>Ibuprofen - pharmacology</topic><topic>Internal Medicine</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine &amp; Public Health</topic><topic>Middle Aged</topic><topic>Models, Biological</topic><topic>Monte Carlo Method</topic><topic>Original Research Article</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacotherapy</topic><topic>Platelet Aggregation - drug effects</topic><topic>Platelet Aggregation Inhibitors - administration &amp; dosage</topic><topic>Platelet Aggregation Inhibitors - pharmacokinetics</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Single-Blind Method</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hong, Ying</creatorcontrib><creatorcontrib>Gengo, Fran M.</creatorcontrib><creatorcontrib>Rainka, Michelle M.</creatorcontrib><creatorcontrib>Bates, Vernice E.</creatorcontrib><creatorcontrib>Mager, Donald E.</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 Central (Corporate)</collection><collection>Docstoc</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical pharmacokinetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hong, Ying</au><au>Gengo, Fran M.</au><au>Rainka, Michelle M.</au><au>Bates, Vernice E.</au><au>Mager, Donald E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Population Pharmacodynamic Modelling of Aspirin- and Ibuprofen-Induced Inhibition of Platelet Aggregation in Healthy Subjects</atitle><jtitle>Clinical pharmacokinetics</jtitle><stitle>Clin Pharmacokinet</stitle><addtitle>Clin Pharmacokinet</addtitle><date>2008-01-01</date><risdate>2008</risdate><volume>47</volume><issue>2</issue><spage>129</spage><epage>137</epage><pages>129-137</pages><issn>0312-5963</issn><eissn>1179-1926</eissn><coden>CPKNDH</coden><abstract>Objective: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. Methods: Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way crossover study. Treatments consisted of single doses of oral aspirin (325 mg) and ibuprofen (400 mg) and concomitant administration of aspirin (325 mg) and ibuprofen (400 mg). Ex vivo whole blood platelet aggregation induced by collagen (1 μg/mL) or arachidonic acid (0.5 mmol/L) was measured by impedance aggregometry. Model development and population parameter estimation were performed using nonlinear mixed-effects modelling implemented in NONMEM. Results: Relatively complete inhibition of platelet aggregation was achieved following aspirin treatment (∼77% inhibition within 2 hours), and return to baseline values occurred within 72–96 hours after dosing. In contrast, treatment with ibuprofen alone or in combination with aspirin produced transient inhibition of platelet aggregation, with complete recovery observed in 6–8 hours. The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (k out ) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h −1 and 0.152 (mg/L) −1 · h −1 , with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. Conclusions: A mechanism-based pharmacodynamic model has been developed that characterizes the anti-platelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>18193919</pmid><doi>10.2165/00003088-200847020-00006</doi><tpages>9</tpages></addata></record>
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subjects Administration, Oral
Adult
Arachidonic Acid - pharmacology
Aspirin - blood
Aspirin - pharmacokinetics
Aspirin - pharmacology
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Collagen - pharmacology
Cross-Over Studies
Cyclooxygenase Inhibitors - administration & dosage
Cyclooxygenase Inhibitors - pharmacokinetics
Cyclooxygenase Inhibitors - pharmacology
Half-Life
Humans
Ibuprofen - blood
Ibuprofen - pharmacokinetics
Ibuprofen - pharmacology
Internal Medicine
Medical sciences
Medicine
Medicine & Public Health
Middle Aged
Models, Biological
Monte Carlo Method
Original Research Article
Pharmacology. Drug treatments
Pharmacology/Toxicology
Pharmacotherapy
Platelet Aggregation - drug effects
Platelet Aggregation Inhibitors - administration & dosage
Platelet Aggregation Inhibitors - pharmacokinetics
Platelet Aggregation Inhibitors - pharmacology
Single-Blind Method
Time Factors
title Population Pharmacodynamic Modelling of Aspirin- and Ibuprofen-Induced Inhibition of Platelet Aggregation in Healthy Subjects
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