Mechanistic in silico modelling of colonic drug absorption

Limited colon absorption is a key factor why controlled release formulation development may fail. In addition, it has been recognized by regulatory agencies that in silico prediction of colon absorption is a gap in the current Biopharmaceutics modelling & simulation capability to predict the in vivo performance of controlled release products. The overall objective of this project is to develop a new mechanistic in silico model for colonic drug absorption. The in-silico model development and validation work will be performed using the AstraZeneca in-house developed PBBM/PBPK tool GI-SIM, but work may also be performed in commercially available software like GastroPlus. This will provide a versatile platform for testing a variety of hypotheses leading to a novel predictive model. Factors that will be considered are colonic dissolution, quantitate solubility data in different biorelevant media including simulated colonic fluids, binding of drugs to components in the colon (e.g., fibers, bacteria), drug degradation by bacteria, distribution and transit effects caused by convection induced by intestinal motility. A unique database with human regional absorption data and an established input parameter dataset from AstraZeneca will allow validation of the new model. The improved understanding generated in the other COLOTAN ESRs will also provide unique input for the model development.