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

• Published in: PloS one Vol. 14; no. 2; p. e0209587
• Main Authors: Kalra, Priyata, Brandl, Julian, Gaub, Thomas, Niederalt, Christoph, Lippert, Jörg, Sahle, Sven, Küpfer, Lars, Kummer, Ursula
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.02.2019; Public Library of Science (PLoS)
• Subjects: Binding sites; Biological response modifiers; Biology and Life Sciences; Cells, Cultured; Cellular communication; Cellular signal transduction; Chemotherapy; Clinical medicine; Computer applications; Computer Simulation; Cytokines; Drug development; Hepatitis; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Immunologic Factors - pharmacokinetics; Immunologic Factors - pharmacology; In vivo methods and tests; Interferon; Interferon alpha; Interferon-alpha - pharmacokinetics; Interferon-alpha - pharmacology; Intracellular; Intracellular signalling; Intravenous administration; Janus Kinases - metabolism; Kinases; Ligands; Liver; Liver - drug effects; Liver - metabolism; Medicine; Medicine and Health Sciences; Models, Biological; Multi-scale models; Patients; Pharmaceuticals; Pharmacodynamics; Pharmacokinetics; Pharmacological research; Pharmacology; Proteins; Research and Analysis Methods; Scale models; Signal Transduction; Software; STAT Transcription Factors - metabolism; Telecommunications systems; Transcription factors; Wireless communications; α-Interferon; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0209587

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.