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.
Highlights
Pleiotropic interferon alpha (IFN-α) belongs to the type I IFNs family
We present a multiscale physiologically-based pharmacokinetic (PBPK)/PD model that simultaneously quantifies the amount of IFN-α reaching the liver in a time-resolved manner, as well as the induced response in the intracellular signalling network
We developed a multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model which simultaneously describes two levels of biological organisation: IFN-α distribution at the organism scale as well as the resulting cellular response in the JAK/STAT pathway
Summary
IFN-α is an extensively used cytokine in clinical medicine, effective in hepatitis C (HCV) and hepatitis B (HBV) treatment over the past 20 years [1,2,3,4,5,6,7,8,9]. Despite its routine application in clinical practice [10], there is incomplete understanding regarding its modes of action and the causality of induced pharmacodynamic effects. One hindrance to discern the molecular response in hepatocytes to IFN-α treatment is that the experimental investigation requires liver biopsies of patients undergoing IFN-α therapy. This is ethically difficult, if not infeasible and would impose a significant burden for the patient [12]
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