A Dynamic Quantitative Systems Pharmacology Model of Inflammatory Bowel Disease: Part 1 – Model Framework

Abstract

A mechanistic, multistate, mathematical model of inflammatory bowel disease (IBD) was developed by including key biological mechanisms in blood and gut, including cell differentiation, cytokine production, and clinical biomarkers. The model structure is consistent between healthy volunteers and IBD disease phenotype, with 24 parameters changed between diseases. Modular nature of the model allows for easy incorporation of new mechanisms or modification of existing interactions. Model simulations for steady-state levels of proteins and cells in the blood and gut using a population approach are consistent with published data. By simulating the response of two clinical biomarkers, C-reactive protein and fecal calprotectin, to parameter perturbations, the model explores hypotheses for possible treatment mechanisms. With additional experimental validation and addition of drug treatments, the model provides a platform to test hypothesis on treatment effects in IBD.