The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I Project is to provide the pharmaceutical industry with improved pre-clinical screening assay for oral drug absorption. Current in vitro methods for characterizing gastrointestinal absorption are based on unreliable assays, with 90% of all drugs developed ultimately failing to enter the market. Practically, these limitations delay the development of critically needed therapeutic drugs and dramatically increase drug prices and health care costs. There is, therefore, a critical need to develop more predictive in vitro testing assays that will allow for early selection of the most promising drug candidates to reduce the number of live animal studies and their associated costs, while accelerating transition from pre-clinical research to early drug development. The technology is based on the discovery, fundamental characterization and bioarchiving of adult canine intestinal stem cell lines, called 3-dimensional (3D) canine intestinal organoids. These miniguts emulate the physiology of the functional intestine much more closely than currently available methods and have the potential to provide superior drug screening over currently used assays. This SBIR Phase I is a proposal to establish that in vitro predictability of oral drug absorption can be improved using canine intestinal organoids vs. standard 2D in vitro assays, such as Caco2 and MDCK cell lines. In Aim 1, the goal is to determine intestinal absorption and permeability of therapeutic drugs as a function of disease and intestinal segment as compared with conventional in vitro models. This will be achieved by quantifying passive and active permeability of drugs, as well as drug transporter expression and function in 3D canine organoids vs. conventional cell systems. In Aim 2, the goal is to determine intestinal metabolism of therapeutic drugs as a function of disease and intestinal segment in canine organoids compared to standard in vitro models. Ultimately, quantitative data generated through these experiments will be imported into a commercial software to simulate the disposition kinetics of a predefined set of candidate drugs. Performances of the model predictions will be evaluated by comparing simulated vs. observed drug kinetic plasma data from the literature for validation purposes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
