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Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel
Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585621/ https://www.ncbi.nlm.nih.gov/pubmed/29696643 http://dx.doi.org/10.1002/cpt.1099 |
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author | Itkonen, Matti K. Tornio, Aleksi Lapatto‐Reiniluoto, Outi Neuvonen, Mikko Neuvonen, Pertti J. Niemi, Mikko Backman, Janne T. |
author_facet | Itkonen, Matti K. Tornio, Aleksi Lapatto‐Reiniluoto, Outi Neuvonen, Mikko Neuvonen, Pertti J. Niemi, Mikko Backman, Janne T. |
author_sort | Itkonen, Matti K. |
collection | PubMed |
description | Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC(0‐∞) of dasabuvir 4.7‐fold; range 2.0–10.1‐fold (P = 8·10(−7)), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC(0‐∞) 3.9‐fold; range 2.1–7.9‐fold (P = 2·10(−6)), compared with ritonavir alone. Ritonavir decreased the AUC(0‐4h) of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response. |
format | Online Article Text |
id | pubmed-6585621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-65856212019-06-27 Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel Itkonen, Matti K. Tornio, Aleksi Lapatto‐Reiniluoto, Outi Neuvonen, Mikko Neuvonen, Pertti J. Niemi, Mikko Backman, Janne T. Clin Pharmacol Ther Research Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC(0‐∞) of dasabuvir 4.7‐fold; range 2.0–10.1‐fold (P = 8·10(−7)), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC(0‐∞) 3.9‐fold; range 2.1–7.9‐fold (P = 2·10(−6)), compared with ritonavir alone. Ritonavir decreased the AUC(0‐4h) of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response. John Wiley and Sons Inc. 2018-08-09 2019-01 /pmc/articles/PMC6585621/ /pubmed/29696643 http://dx.doi.org/10.1002/cpt.1099 Text en © 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics 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 | Research Itkonen, Matti K. Tornio, Aleksi Lapatto‐Reiniluoto, Outi Neuvonen, Mikko Neuvonen, Pertti J. Niemi, Mikko Backman, Janne T. Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel |
title | Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel |
title_full | Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel |
title_fullStr | Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel |
title_full_unstemmed | Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel |
title_short | Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel |
title_sort | clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585621/ https://www.ncbi.nlm.nih.gov/pubmed/29696643 http://dx.doi.org/10.1002/cpt.1099 |
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