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Isavuconazole Pharmacokinetics and Pharmacodynamics in Children

Isavuconazole is a broad-spectrum azole anti-fungal not yet approved in children. We conducted a retrospective, single-center review of isavuconazole use and routine therapeutic drug monitoring in pediatric patients, extracting demographic, dosing, concentration, mortality and hepatoxicity data. We...

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Autores principales: Elhence, Hirsh, Mongkolrattanothai, Kanokporn, Mohandas, Sindhu, Neely, Michael N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865364/
https://www.ncbi.nlm.nih.gov/pubmed/36678704
http://dx.doi.org/10.3390/pharmaceutics15010075
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author Elhence, Hirsh
Mongkolrattanothai, Kanokporn
Mohandas, Sindhu
Neely, Michael N.
author_facet Elhence, Hirsh
Mongkolrattanothai, Kanokporn
Mohandas, Sindhu
Neely, Michael N.
author_sort Elhence, Hirsh
collection PubMed
description Isavuconazole is a broad-spectrum azole anti-fungal not yet approved in children. We conducted a retrospective, single-center review of isavuconazole use and routine therapeutic drug monitoring in pediatric patients, extracting demographic, dosing, concentration, mortality and hepatoxicity data. We constructed a nonparametric population model using Pmetrics. Of 26 patients, 19 (73%) were male. The mean (SD) age and weight were 12.7 (5.5) years and 50.9 (26.8) kg. Eighty percent received between 9.7 and 10.6 mg/kg per dose. Ten (38%) subjects had proven fungal disease and eight (31%) had probable disease, mostly with Candida and Aspergillus spp. The predicted steady-state isavuconazole concentrations in our patients were similar to previous reports in children and adults, and simulations with the proposed dosing of 10 mg/kg/dose every 8 h for 2 days followed by once daily maintenance matched effective adult exposures. Attributable mortality (5 of 11 deaths) was associated with steady-state daily AUC < 60 mg∗h/L and higher AST/ALT with trough concentrations > 5 mg/L. Neither dose nor trough alone correlated well with AUC, but AUC can be estimated with one sample 10 h after the first maintenance dose or a trough concentration, if combined with a Bayesian approach or a peak and trough without a Bayesian approach.
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spelling pubmed-98653642023-01-22 Isavuconazole Pharmacokinetics and Pharmacodynamics in Children Elhence, Hirsh Mongkolrattanothai, Kanokporn Mohandas, Sindhu Neely, Michael N. Pharmaceutics Article Isavuconazole is a broad-spectrum azole anti-fungal not yet approved in children. We conducted a retrospective, single-center review of isavuconazole use and routine therapeutic drug monitoring in pediatric patients, extracting demographic, dosing, concentration, mortality and hepatoxicity data. We constructed a nonparametric population model using Pmetrics. Of 26 patients, 19 (73%) were male. The mean (SD) age and weight were 12.7 (5.5) years and 50.9 (26.8) kg. Eighty percent received between 9.7 and 10.6 mg/kg per dose. Ten (38%) subjects had proven fungal disease and eight (31%) had probable disease, mostly with Candida and Aspergillus spp. The predicted steady-state isavuconazole concentrations in our patients were similar to previous reports in children and adults, and simulations with the proposed dosing of 10 mg/kg/dose every 8 h for 2 days followed by once daily maintenance matched effective adult exposures. Attributable mortality (5 of 11 deaths) was associated with steady-state daily AUC < 60 mg∗h/L and higher AST/ALT with trough concentrations > 5 mg/L. Neither dose nor trough alone correlated well with AUC, but AUC can be estimated with one sample 10 h after the first maintenance dose or a trough concentration, if combined with a Bayesian approach or a peak and trough without a Bayesian approach. MDPI 2022-12-26 /pmc/articles/PMC9865364/ /pubmed/36678704 http://dx.doi.org/10.3390/pharmaceutics15010075 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Elhence, Hirsh
Mongkolrattanothai, Kanokporn
Mohandas, Sindhu
Neely, Michael N.
Isavuconazole Pharmacokinetics and Pharmacodynamics in Children
title Isavuconazole Pharmacokinetics and Pharmacodynamics in Children
title_full Isavuconazole Pharmacokinetics and Pharmacodynamics in Children
title_fullStr Isavuconazole Pharmacokinetics and Pharmacodynamics in Children
title_full_unstemmed Isavuconazole Pharmacokinetics and Pharmacodynamics in Children
title_short Isavuconazole Pharmacokinetics and Pharmacodynamics in Children
title_sort isavuconazole pharmacokinetics and pharmacodynamics in children
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865364/
https://www.ncbi.nlm.nih.gov/pubmed/36678704
http://dx.doi.org/10.3390/pharmaceutics15010075
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