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Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach

The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different phy...

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Autores principales: Kalra, Priyata, Brandl, Julian, Gaub, Thomas, Niederalt, Christoph, Lippert, Jörg, Sahle, Sven, Küpfer, Lars, Kummer, Ursula
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374012/
https://www.ncbi.nlm.nih.gov/pubmed/30759154
http://dx.doi.org/10.1371/journal.pone.0209587
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author Kalra, Priyata
Brandl, Julian
Gaub, Thomas
Niederalt, Christoph
Lippert, Jörg
Sahle, Sven
Küpfer, Lars
Kummer, Ursula
author_facet Kalra, Priyata
Brandl, Julian
Gaub, Thomas
Niederalt, Christoph
Lippert, Jörg
Sahle, Sven
Küpfer, Lars
Kummer, Ursula
author_sort Kalra, Priyata
collection PubMed
description The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design.
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spelling pubmed-63740122019-03-01 Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach Kalra, Priyata Brandl, Julian Gaub, Thomas Niederalt, Christoph Lippert, Jörg Sahle, Sven Küpfer, Lars Kummer, Ursula PLoS One Research Article The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design. Public Library of Science 2019-02-13 /pmc/articles/PMC6374012/ /pubmed/30759154 http://dx.doi.org/10.1371/journal.pone.0209587 Text en © 2019 Kalra et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kalra, Priyata
Brandl, Julian
Gaub, Thomas
Niederalt, Christoph
Lippert, Jörg
Sahle, Sven
Küpfer, Lars
Kummer, Ursula
Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach
title Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach
title_full Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach
title_fullStr Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach
title_full_unstemmed Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach
title_short Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach
title_sort quantitative systems pharmacology of interferon alpha administration: a multi-scale approach
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374012/
https://www.ncbi.nlm.nih.gov/pubmed/30759154
http://dx.doi.org/10.1371/journal.pone.0209587
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