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Verfasst von:Kalra, Priyata [VerfasserIn]   i
 Sahle, Sven [VerfasserIn]   i
 Kummer, Ursula [VerfasserIn]   i
Titel:Quantitative systems pharmacology of interferon alpha administration
Titelzusatz:A multi-scale approach
Verf.angabe:Priyata Kalra, Julian Brandl, Thomas Gaub, Christoph Niederalt, Jörg Lippert, Sven Sahle, Lars Küpfer, Ursula Kummer
E-Jahr:2019
Jahr:February 13, 2019
Umfang:21 S.
Fussnoten:Gesehen am 31.07.2019
Titel Quelle:Enthalten in: PLOS ONE
Ort Quelle:San Francisco, California, US : PLOS, 2006
Jahr Quelle:2019
Band/Heft Quelle:14(2019,2) Artikel-Nummer e0209587, 21 Seiten
ISSN Quelle:1932-6203
Abstract: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.
DOI:doi:10.1371/journal.pone.0209587
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext: https://doi.org/10.1371/journal.pone.0209587
 Volltext: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209587
 DOI: https://doi.org/10.1371/journal.pone.0209587
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Blood plasma
 Drug administration
 Hepatocytes
 Interferons
 Intracellular receptors
 Pharmacokinetics
 Pharmacology
 Simulation and modeling
K10plus-PPN:1670318621
Verknüpfungen:→ Zeitschrift

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