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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...

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Autores principales: Itkonen, Matti K., Tornio, Aleksi, Lapatto‐Reiniluoto, Outi, Neuvonen, Mikko, Neuvonen, Pertti J., Niemi, Mikko, Backman, Janne T.
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/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.
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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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