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Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment

Isavuconazole, administered as the prodrug isavuconazonium sulfate, was recently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population ph...

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Autores principales: Desai, Amit, Schmitt-Hoffmann, Anne-Hortense, Mujais, Salim, Townsend, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862513/
https://www.ncbi.nlm.nih.gov/pubmed/26953193
http://dx.doi.org/10.1128/AAC.02942-15
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author Desai, Amit
Schmitt-Hoffmann, Anne-Hortense
Mujais, Salim
Townsend, Robert
author_facet Desai, Amit
Schmitt-Hoffmann, Anne-Hortense
Mujais, Salim
Townsend, Robert
author_sort Desai, Amit
collection PubMed
description Isavuconazole, administered as the prodrug isavuconazonium sulfate, was recently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral administration data from two hepatic studies, and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 liters/h (5th and 95th percentiles: 2.0 and 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively. Peripheral volume of distribution increased with body mass index. Simulations of mean concentration time profiles to steady state showed less than a 2-fold increase in mean trough concentrations for subjects with mild and moderate hepatic impairment compared with healthy subjects. After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies. Due to the <2-fold increase in trough concentrations and the established safety margin, dose adjustment appears to be unnecessary in subjects with mild or moderate hepatic impairment.
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spelling pubmed-48625132016-06-09 Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment Desai, Amit Schmitt-Hoffmann, Anne-Hortense Mujais, Salim Townsend, Robert Antimicrob Agents Chemother Pharmacology Isavuconazole, administered as the prodrug isavuconazonium sulfate, was recently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral administration data from two hepatic studies, and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 liters/h (5th and 95th percentiles: 2.0 and 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively. Peripheral volume of distribution increased with body mass index. Simulations of mean concentration time profiles to steady state showed less than a 2-fold increase in mean trough concentrations for subjects with mild and moderate hepatic impairment compared with healthy subjects. After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies. Due to the <2-fold increase in trough concentrations and the established safety margin, dose adjustment appears to be unnecessary in subjects with mild or moderate hepatic impairment. American Society for Microbiology 2016-04-22 /pmc/articles/PMC4862513/ /pubmed/26953193 http://dx.doi.org/10.1128/AAC.02942-15 Text en Copyright © 2016 Desai et al. http://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 (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Pharmacology
Desai, Amit
Schmitt-Hoffmann, Anne-Hortense
Mujais, Salim
Townsend, Robert
Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment
title Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment
title_full Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment
title_fullStr Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment
title_full_unstemmed Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment
title_short Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment
title_sort population pharmacokinetics of isavuconazole in subjects with mild or moderate hepatic impairment
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862513/
https://www.ncbi.nlm.nih.gov/pubmed/26953193
http://dx.doi.org/10.1128/AAC.02942-15
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