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

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.

Tools and Data Towards Supporting Quantitative Systems Pharmacology of the Eye – An Overview

“…Considering the whole body, such multiscale models allow to simultaneously describe drug exposure in plasma as well as the resulting drug-induced response within the cellular networks. QSP models have amongst others been used to simulate cellular signalling models within the context of whole-body PBPK models (77,78). Likewise, metabolic network models have been integrated in PBPK models (79,80).…”

Mathematical Modeling for Hepatitis B Virus: Would Spatial Effects Play a Role and How to Model It?

“…input from pharmacokinetic models which target at the whole organism (Kalra et al, 2019)-providing a method for predicting success or failure of such efforts. As spatial distribution effects on HBV replicating, propagation and spreading through intercellular spatial arrangements are needed to be studied both in mathematical and animal models.…”

Multi-scale modeling of drug binding kinetics to predict drug efficacy

“…PD describes how the given drug concentration in its target tissue elicits its effects. While multi-scale models that describe both PK and PD in mechanistic detail have been developed [13], we discuss PK and PD approaches separately for clarity. PK describes the "movement" of the drug in the human body, often subdivided in compartments.…”