Algorithms and methodological challenges in the development and application of quantitative systems pharmacology models: a case study in type 2 diabetes

Abstract Quantitative systems pharmacology (QSP) is a relatively new modelling discipline, formed within the ever-growing domain of model-informed drug development and actively evolving throughout the last decade. This modelling technique is based on the systems analysis and is used to get a quantitative rather than qualitative understanding of systems dynamics and explore the mechanisms of action of a drug. However, there is no well-defined methodology for the QSP model development, which significantly complicates the practical application of these models. In the current work, we overview the existing mathematical models of antidiabetic therapies and propose a modelling method, which overcomes common limitations and is able to produce a physiologically based mechanistic model describing gliflozin action in type 2 diabetes mellitus. From the practical standpoint, sensitivity analysis preformed in this work helped to reveal subpopulation of patients with better response to gliflozin therapy.