Only 13% of investigational drugs that enter clinical trials make it to approval. Seventy-five percent of these failures are due to either unexpected toxicity or lack of efficacy discovered in phase I and II clinical trials. This high failure rate o drugs in late stage development is a symptom of the inadequacy of pre- clinical animal models to accurately predict human biology. Technologies based on human organ systems in vitro has the potential to overcome these limitations by enabling human relevant physiology to be studied earlier in the drug discovery process. In other words, development of more physiologically relevant in vitro systems grounded in human biology rather than animal biology could potentially bring drugs to market faster with fewer failures. The purpose of this work is to produce cryopreserved adult human small intestinal cells and incorporate those cells into an intestine-hepatocyte co-culture system that will better recapitulate human drug and toxicant metabolism in an in-vitro system. The goals of this proposed project are twofold: 1) Test feasibility of a novl approach for cryopreservation and reanimation of human small intestinal epithelium from either cadaver derived or fresh derived jejunum tissue; 2) Test feasibility of a multi-tissue organ systems incorporating both intestine and liver metabolism to enable a comprehensive benchtop in vitro metabolism model using entirely human- derived products for pharmaceutical efficacy and safety testing as well as industrial chemical safety testing
It is well known that current early stage drug development model systems, consisting mainly of static tumor-derived cell cultures and rodent animal models, poorly predict both efficacy and safety of new therapeutics. This is in part due to failure of the models to replicate in vivo pharmacokinetics. In this study, Bench-top human metabolism system for improved IVIVE in drug development we will create a user-friendly in vitro pharmacokinetic solution in a disposable unit that bypasses any need for large capital investment and intensive technical training. Our system is comprised of both intestine and liver cells representing over 90% of the metabolic activity in the human body. The capability of performing more in vivo-like humanized experiments in early drug development stages will be more predictive of both drug efficacy and safety and ultimately reduce late-stage failures.
