Cargando…

A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients

Understanding antibiotic concentration-time profiles in the central nervous system (CNS) is crucial to treat severe life-threatening CNS infections, such as nosocomial ventriculitis or meningitis. Yet CNS distribution is likely to be altered in patients with brain damage and infection/inflammation....

Descripción completa

Detalles Bibliográficos
Autores principales: Chauzy, Alexia, Bouchène, Salim, Aranzana-Climent, Vincent, Clarhaut, Jonathan, Adier, Christophe, Grégoire, Nicolas, Couet, William, Dahyot-Fizelier, Claire, Marchand, Sandrine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598284/
https://www.ncbi.nlm.nih.gov/pubmed/36289950
http://dx.doi.org/10.3390/antibiotics11101293
_version_ 1784816295149043712
author Chauzy, Alexia
Bouchène, Salim
Aranzana-Climent, Vincent
Clarhaut, Jonathan
Adier, Christophe
Grégoire, Nicolas
Couet, William
Dahyot-Fizelier, Claire
Marchand, Sandrine
author_facet Chauzy, Alexia
Bouchène, Salim
Aranzana-Climent, Vincent
Clarhaut, Jonathan
Adier, Christophe
Grégoire, Nicolas
Couet, William
Dahyot-Fizelier, Claire
Marchand, Sandrine
author_sort Chauzy, Alexia
collection PubMed
description Understanding antibiotic concentration-time profiles in the central nervous system (CNS) is crucial to treat severe life-threatening CNS infections, such as nosocomial ventriculitis or meningitis. Yet CNS distribution is likely to be altered in patients with brain damage and infection/inflammation. Our objective was to develop a physiologically based pharmacokinetic (PBPK) model to predict brain concentration-time profiles of antibiotics and to simulate the impact of pathophysiological changes on CNS profiles. A minimal PBPK model consisting of three physiological brain compartments was developed from metronidazole concentrations previously measured in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) of eight brain-injured patients. Volumes and blood flows were fixed to their physiological value obtained from the literature. Diffusion clearances characterizing transport across the blood–brain barrier and blood–CSF barrier were estimated from system- and drug-specific parameters and were confirmed from a Caco-2 model. The model described well unbound metronidazole pharmacokinetic profiles in plasma, ECF and CSF. Simulations showed that with metronidazole, an antibiotic with extensive CNS distribution simply governed by passive diffusion, pathophysiological alterations of membrane permeability, brain ECF volume or cerebral blood flow would have no effect on ECF or CSF pharmacokinetic profiles. This work will serve as a starting point for the development of a new PBPK model to describe the CNS distribution of antibiotics with more limited permeability for which pathophysiological conditions are expected to have a greater effect.
format Online
Article
Text
id pubmed-9598284
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-95982842022-10-27 A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients Chauzy, Alexia Bouchène, Salim Aranzana-Climent, Vincent Clarhaut, Jonathan Adier, Christophe Grégoire, Nicolas Couet, William Dahyot-Fizelier, Claire Marchand, Sandrine Antibiotics (Basel) Article Understanding antibiotic concentration-time profiles in the central nervous system (CNS) is crucial to treat severe life-threatening CNS infections, such as nosocomial ventriculitis or meningitis. Yet CNS distribution is likely to be altered in patients with brain damage and infection/inflammation. Our objective was to develop a physiologically based pharmacokinetic (PBPK) model to predict brain concentration-time profiles of antibiotics and to simulate the impact of pathophysiological changes on CNS profiles. A minimal PBPK model consisting of three physiological brain compartments was developed from metronidazole concentrations previously measured in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) of eight brain-injured patients. Volumes and blood flows were fixed to their physiological value obtained from the literature. Diffusion clearances characterizing transport across the blood–brain barrier and blood–CSF barrier were estimated from system- and drug-specific parameters and were confirmed from a Caco-2 model. The model described well unbound metronidazole pharmacokinetic profiles in plasma, ECF and CSF. Simulations showed that with metronidazole, an antibiotic with extensive CNS distribution simply governed by passive diffusion, pathophysiological alterations of membrane permeability, brain ECF volume or cerebral blood flow would have no effect on ECF or CSF pharmacokinetic profiles. This work will serve as a starting point for the development of a new PBPK model to describe the CNS distribution of antibiotics with more limited permeability for which pathophysiological conditions are expected to have a greater effect. MDPI 2022-09-22 /pmc/articles/PMC9598284/ /pubmed/36289950 http://dx.doi.org/10.3390/antibiotics11101293 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
Chauzy, Alexia
Bouchène, Salim
Aranzana-Climent, Vincent
Clarhaut, Jonathan
Adier, Christophe
Grégoire, Nicolas
Couet, William
Dahyot-Fizelier, Claire
Marchand, Sandrine
A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients
title A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients
title_full A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients
title_fullStr A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients
title_full_unstemmed A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients
title_short A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients
title_sort minimal physiologically based pharmacokinetic model to characterize cns distribution of metronidazole in neuro care icu patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598284/
https://www.ncbi.nlm.nih.gov/pubmed/36289950
http://dx.doi.org/10.3390/antibiotics11101293
work_keys_str_mv AT chauzyalexia aminimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT bouchenesalim aminimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT aranzanaclimentvincent aminimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT clarhautjonathan aminimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT adierchristophe aminimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT gregoirenicolas aminimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT couetwilliam aminimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT dahyotfizelierclaire aminimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT marchandsandrine aminimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT chauzyalexia minimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT bouchenesalim minimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT aranzanaclimentvincent minimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT clarhautjonathan minimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT adierchristophe minimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT gregoirenicolas minimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT couetwilliam minimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT dahyotfizelierclaire minimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients
AT marchandsandrine minimalphysiologicallybasedpharmacokineticmodeltocharacterizecnsdistributionofmetronidazoleinneurocareicupatients