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Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients

AIMS: To characterize ticagrelor exposure‐response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using nonlinear mixed effects modelling and simulation. METHODS: Platelet function data were integrated with plas...

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Autores principales: Åstrand, Magnus, Amilon, Carl, Röshammar, Daniel, Himmelmann, Anders, Angiolillo, Dominick J., Storey, Robert F., Gurbel, Paul A., Bonaca, Marc P., Hamrén, Bengt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339964/
https://www.ncbi.nlm.nih.gov/pubmed/30414387
http://dx.doi.org/10.1111/bcp.13812
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author Åstrand, Magnus
Amilon, Carl
Röshammar, Daniel
Himmelmann, Anders
Angiolillo, Dominick J.
Storey, Robert F.
Gurbel, Paul A.
Bonaca, Marc P.
Hamrén, Bengt
author_facet Åstrand, Magnus
Amilon, Carl
Röshammar, Daniel
Himmelmann, Anders
Angiolillo, Dominick J.
Storey, Robert F.
Gurbel, Paul A.
Bonaca, Marc P.
Hamrén, Bengt
author_sort Åstrand, Magnus
collection PubMed
description AIMS: To characterize ticagrelor exposure‐response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using nonlinear mixed effects modelling and simulation. METHODS: Platelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR‐C1249010XX in a population pharmacokinetic (PK) and pharmacodynamic (PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS‐TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily. RESULTS: Platelet inhibition by ticagrelor was described by a sigmoidal E(max) model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol l(–1). Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak‐to‐trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations. CONCLUSIONS: In patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modelled doses <60 mg, the response is reduced overall, more variable between patients, and patients will display greater peak‐to‐trough variability.
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spelling pubmed-63399642019-01-24 Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients Åstrand, Magnus Amilon, Carl Röshammar, Daniel Himmelmann, Anders Angiolillo, Dominick J. Storey, Robert F. Gurbel, Paul A. Bonaca, Marc P. Hamrén, Bengt Br J Clin Pharmacol Original Articles AIMS: To characterize ticagrelor exposure‐response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using nonlinear mixed effects modelling and simulation. METHODS: Platelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR‐C1249010XX in a population pharmacokinetic (PK) and pharmacodynamic (PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS‐TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily. RESULTS: Platelet inhibition by ticagrelor was described by a sigmoidal E(max) model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol l(–1). Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak‐to‐trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations. CONCLUSIONS: In patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modelled doses <60 mg, the response is reduced overall, more variable between patients, and patients will display greater peak‐to‐trough variability. John Wiley and Sons Inc. 2018-12-18 2019-02 /pmc/articles/PMC6339964/ /pubmed/30414387 http://dx.doi.org/10.1111/bcp.13812 Text en © 2018 Astrazeneca. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Åstrand, Magnus
Amilon, Carl
Röshammar, Daniel
Himmelmann, Anders
Angiolillo, Dominick J.
Storey, Robert F.
Gurbel, Paul A.
Bonaca, Marc P.
Hamrén, Bengt
Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients
title Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients
title_full Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients
title_fullStr Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients
title_full_unstemmed Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients
title_short Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients
title_sort pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339964/
https://www.ncbi.nlm.nih.gov/pubmed/30414387
http://dx.doi.org/10.1111/bcp.13812
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