A Quantitative Systems Pharmacology Model for the Key Interleukins Involved in Crohn's Disease

Abstract

Crohn's disease (CD) is a complex inflammatory bowel disease whose pathogenesis appears to involve several immunologic defects causing functional impairment of the gut. Its complexity and the reported loss of effectiveness over time of standard of care together with the increase in its worldwide incidence require the application of techniques aiming to find new therapeutic strategies. Currently, systems pharmacology modeling has been gaining importance as it integrates the available knowledge of the system into a single computational model. In this work, the following workflow for robust application of systems pharmacology modeling was followed: 1) scope definition; 2) species selection and circulating plasma levels based on a search in the literature; 3) representation of model topology and parametrization of the interactions, after literature data extraction and curation, and the implementation of ordinary differential equations in SimBiology (MATLAB version R2018b); and 4) model curation and evaluation by visual comparison of simulated interleukin (IL) concentrations with the reported levels in plasma, and sensitivity analysis performed to confirm model robustness and identify the most influential parameters. Finally, 5) exposure to two dose levels of recombinant human IL10 was evaluated by simulation and comparison with reported clinical study results. In summary, we present a quantitative systems pharmacology model for the main ILs involved in CD developed using a standardized methodology and supported by a comprehensive repository summarizing the most relevant literature in the field. However, it has to be taken into account that external validation is still pending as available clinical data were primarily used for model training. SIGNIFICANCE STATEMENT: Crohn's disease (CD) is a complex heterogeneous inflammatory bowel disorder. Systems pharmacology modeling offers a great opportunity for integration of the available knowledge on the disease using a computational framework. As a result of this work, a comprehensive repository along with a quantitative systems pharmacology model for the main interleukins involved in CD is provided. This model is useful for the in silico evaluation of biomarkers and potential therapeutic targets and can be adapted to address research gaps regarding CD.