Cargando…
Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi
Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700339/ https://www.ncbi.nlm.nih.gov/pubmed/28923872 http://dx.doi.org/10.1128/AAC.01034-17 |
_version_ | 1783281107308904448 |
---|---|
author | Desai, Amit V. Kovanda, Laura L. Hope, William W. Andes, David Mouton, Johan W. Kowalski, Donna L. Townsend, Robert W. Mujais, Salim Bonate, Peter L. |
author_facet | Desai, Amit V. Kovanda, Laura L. Hope, William W. Andes, David Mouton, Johan W. Kowalski, Donna L. Townsend, Robert W. Mujais, Salim Bonate, Peter L. |
author_sort | Desai, Amit V. |
collection | PubMed |
description | Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole. |
format | Online Article Text |
id | pubmed-5700339 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-57003392017-12-01 Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi Desai, Amit V. Kovanda, Laura L. Hope, William W. Andes, David Mouton, Johan W. Kowalski, Donna L. Townsend, Robert W. Mujais, Salim Bonate, Peter L. Antimicrob Agents Chemother Clinical Therapeutics Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole. American Society for Microbiology 2017-11-22 /pmc/articles/PMC5700339/ /pubmed/28923872 http://dx.doi.org/10.1128/AAC.01034-17 Text en Copyright © 2017 Desai et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Clinical Therapeutics Desai, Amit V. Kovanda, Laura L. Hope, William W. Andes, David Mouton, Johan W. Kowalski, Donna L. Townsend, Robert W. Mujais, Salim Bonate, Peter L. Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi |
title | Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi |
title_full | Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi |
title_fullStr | Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi |
title_full_unstemmed | Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi |
title_short | Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi |
title_sort | exposure-response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi |
topic | Clinical Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700339/ https://www.ncbi.nlm.nih.gov/pubmed/28923872 http://dx.doi.org/10.1128/AAC.01034-17 |
work_keys_str_mv | AT desaiamitv exposureresponserelationshipsforisavuconazoleinpatientswithinvasiveaspergillosisandotherfilamentousfungi AT kovandalaural exposureresponserelationshipsforisavuconazoleinpatientswithinvasiveaspergillosisandotherfilamentousfungi AT hopewilliamw exposureresponserelationshipsforisavuconazoleinpatientswithinvasiveaspergillosisandotherfilamentousfungi AT andesdavid exposureresponserelationshipsforisavuconazoleinpatientswithinvasiveaspergillosisandotherfilamentousfungi AT moutonjohanw exposureresponserelationshipsforisavuconazoleinpatientswithinvasiveaspergillosisandotherfilamentousfungi AT kowalskidonnal exposureresponserelationshipsforisavuconazoleinpatientswithinvasiveaspergillosisandotherfilamentousfungi AT townsendrobertw exposureresponserelationshipsforisavuconazoleinpatientswithinvasiveaspergillosisandotherfilamentousfungi AT mujaissalim exposureresponserelationshipsforisavuconazoleinpatientswithinvasiveaspergillosisandotherfilamentousfungi AT bonatepeterl exposureresponserelationshipsforisavuconazoleinpatientswithinvasiveaspergillosisandotherfilamentousfungi |