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Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects

This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days load...

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Autores principales: Desai, Amit, Yamazaki, Takao, Dietz, Albert J., Kowalski, Donna, Lademacher, Christopher, Pearlman, Helene, Akhtar, Shahzad, Townsend, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298089/
https://www.ncbi.nlm.nih.gov/pubmed/27278712
http://dx.doi.org/10.1002/cpdd.283
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author Desai, Amit
Yamazaki, Takao
Dietz, Albert J.
Kowalski, Donna
Lademacher, Christopher
Pearlman, Helene
Akhtar, Shahzad
Townsend, Robert
author_facet Desai, Amit
Yamazaki, Takao
Dietz, Albert J.
Kowalski, Donna
Lademacher, Christopher
Pearlman, Helene
Akhtar, Shahzad
Townsend, Robert
author_sort Desai, Amit
collection PubMed
description This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration‐time curves from time 0 to infinity of S‐ and R‐warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S‐ and R‐warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment‐emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics.
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spelling pubmed-52980892017-02-22 Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects Desai, Amit Yamazaki, Takao Dietz, Albert J. Kowalski, Donna Lademacher, Christopher Pearlman, Helene Akhtar, Shahzad Townsend, Robert Clin Pharmacol Drug Dev Articles This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration‐time curves from time 0 to infinity of S‐ and R‐warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S‐ and R‐warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment‐emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics. John Wiley and Sons Inc. 2016-08-04 2017 /pmc/articles/PMC5298089/ /pubmed/27278712 http://dx.doi.org/10.1002/cpdd.283 Text en © 2016 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Articles
Desai, Amit
Yamazaki, Takao
Dietz, Albert J.
Kowalski, Donna
Lademacher, Christopher
Pearlman, Helene
Akhtar, Shahzad
Townsend, Robert
Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects
title Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects
title_full Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects
title_fullStr Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects
title_full_unstemmed Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects
title_short Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects
title_sort pharmacokinetic and pharmacodynamic evaluation of the drug‐drug interaction between isavuconazole and warfarin in healthy subjects
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298089/
https://www.ncbi.nlm.nih.gov/pubmed/27278712
http://dx.doi.org/10.1002/cpdd.283
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