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Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2

We extend our established agent-based multiscale computational model of infection of lung tissue by SARS-CoV-2 to include pharmacokinetic and pharmacodynamic models of remdesivir. We model remdesivir treatment for COVID-19; however, our methods are general to other viral infections and antiviral the...

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Autores principales: Ferrari Gianlupi, Juliano, Mapder, Tarunendu, Sego, T. J., Sluka, James P., Quinney, Sara K., Craig, Morgan, Stratford, Robert E., Glazier, James A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953050/
https://www.ncbi.nlm.nih.gov/pubmed/35337012
http://dx.doi.org/10.3390/v14030605
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author Ferrari Gianlupi, Juliano
Mapder, Tarunendu
Sego, T. J.
Sluka, James P.
Quinney, Sara K.
Craig, Morgan
Stratford, Robert E.
Glazier, James A.
author_facet Ferrari Gianlupi, Juliano
Mapder, Tarunendu
Sego, T. J.
Sluka, James P.
Quinney, Sara K.
Craig, Morgan
Stratford, Robert E.
Glazier, James A.
author_sort Ferrari Gianlupi, Juliano
collection PubMed
description We extend our established agent-based multiscale computational model of infection of lung tissue by SARS-CoV-2 to include pharmacokinetic and pharmacodynamic models of remdesivir. We model remdesivir treatment for COVID-19; however, our methods are general to other viral infections and antiviral therapies. We investigate the effects of drug potency, drug dosing frequency, treatment initiation delay, antiviral half-life, and variability in cellular uptake and metabolism of remdesivir and its active metabolite on treatment outcomes in a simulated patch of infected epithelial tissue. Non-spatial deterministic population models which treat all cells of a given class as identical can clarify how treatment dosage and timing influence treatment efficacy. However, they do not reveal how cell-to-cell variability affects treatment outcomes. Our simulations suggest that for a given treatment regime, including cell-to-cell variation in drug uptake, permeability and metabolism increase the likelihood of uncontrolled infection as the cells with the lowest internal levels of antiviral act as super-spreaders within the tissue. The model predicts substantial variability in infection outcomes between similar tissue patches for different treatment options. In models with cellular metabolic variability, antiviral doses have to be increased significantly (>50% depending on simulation parameters) to achieve the same treatment results as with the homogeneous cellular metabolism.
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spelling pubmed-89530502022-03-26 Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2 Ferrari Gianlupi, Juliano Mapder, Tarunendu Sego, T. J. Sluka, James P. Quinney, Sara K. Craig, Morgan Stratford, Robert E. Glazier, James A. Viruses Article We extend our established agent-based multiscale computational model of infection of lung tissue by SARS-CoV-2 to include pharmacokinetic and pharmacodynamic models of remdesivir. We model remdesivir treatment for COVID-19; however, our methods are general to other viral infections and antiviral therapies. We investigate the effects of drug potency, drug dosing frequency, treatment initiation delay, antiviral half-life, and variability in cellular uptake and metabolism of remdesivir and its active metabolite on treatment outcomes in a simulated patch of infected epithelial tissue. Non-spatial deterministic population models which treat all cells of a given class as identical can clarify how treatment dosage and timing influence treatment efficacy. However, they do not reveal how cell-to-cell variability affects treatment outcomes. Our simulations suggest that for a given treatment regime, including cell-to-cell variation in drug uptake, permeability and metabolism increase the likelihood of uncontrolled infection as the cells with the lowest internal levels of antiviral act as super-spreaders within the tissue. The model predicts substantial variability in infection outcomes between similar tissue patches for different treatment options. In models with cellular metabolic variability, antiviral doses have to be increased significantly (>50% depending on simulation parameters) to achieve the same treatment results as with the homogeneous cellular metabolism. MDPI 2022-03-14 /pmc/articles/PMC8953050/ /pubmed/35337012 http://dx.doi.org/10.3390/v14030605 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
Ferrari Gianlupi, Juliano
Mapder, Tarunendu
Sego, T. J.
Sluka, James P.
Quinney, Sara K.
Craig, Morgan
Stratford, Robert E.
Glazier, James A.
Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2
title Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2
title_full Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2
title_fullStr Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2
title_full_unstemmed Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2
title_short Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2
title_sort multiscale model of antiviral timing, potency, and heterogeneity effects on an epithelial tissue patch infected by sars-cov-2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953050/
https://www.ncbi.nlm.nih.gov/pubmed/35337012
http://dx.doi.org/10.3390/v14030605
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