Grant: Collaborative Health Research Projects (NSERC partnered)

Poor intestinal absorption is a major bottleneck in drug discovery as promising new chemical entities often lack suitable amphiphilic balance required for absorption. No one knows how many acceptable candidates have been discarded from the discovery pipeline although their bioavailability could have been significantly improved. Inappropriate in vitro prediction of drug bioavailability is suspected as one of the reasons explaining the rejection of many promising drug candidates from development after time and millions invested in research. The challenge is, thus, to provide just-in time information about drug-like properties to orient the medicinal chemistry lead optimization effort. Parallel artificial membrane permeability assay (PAMPA) is a well-established and simple in vitro model that however lacks biological relevance and reliability. It assesses passive intestinal permeation - the principal route for drug absorption. The objectives of our project are (1) to enhance the PAMPA technology by developing new membranes more representative of the gut cell lipid walls and (2) to make it amenable to HTS and non-specialized lab personnel. We will thus develop phospholipid floating membranes on polymer cushion amenable to Franz cells and multi-well plate setup. This project, in collaboration with an industrial partner, combines a robust technology well-known in the pharmaceutical field to a recent advance in bilayer fluidity devices (polymer-supported membranes) to develop a new assay of drug permeability. It is enabled by the combination of expertises in lipid physicochemistry, polymer science and biopharmacy. The use of this new PAMPA in R&D labs should accelerate the discovery of new drug therapies, reduce the number of discarded promising drugs, and provide more drugs with improved bioavailability and reduced risks of side effects due to too high dosage. The impact on the health of the Canadians should be major - less people should suffer of side effects, and more drug therapies should be available for the treatment of diseases that are affecting the population. Economically, our project will have a positively impact the Canadian pharmaceutical industry and health system.