Preclinical Development – Chemical
2019 PharmSci 360
Availability of human primary cell-based 3D small intestinal microtissues that recapitulate structural and functional mimicry with the in vivo counterpart is critical to obtain reproducible in vitro testing tool to predict the safety and bioavailability of compounds intended for orally administration and other xenobiotics. These 3D intestinal tissue models will also bridge the gap in preclinical testing to predict safety of compounds intended for oral administration. Data from a panel of 30 benchmark drugs with known human absorption values that were. evaluated on the intestinal tissue model will be presented. Study results of drug-drug interactions and drug metabolism will be shared. Furthermore, the functionality and limitations of a novel in vitro 3D primary human small intestine cell-based tissue models for GI toxicity studies will be discussed. The characterization of the reconstructed 3D intestinal tissue model including differentiation and cellular phenotypes, drug transporters and metabolizing enzymes gene expression levels, and biomarkers that can better predict drug bioavailability and human GI toxicity compared to preclinical animal models such as rat and dogs will be highlighted. Overall, the utility of the intestinal tissue platform to 1) rank order the permeability of compounds and 2) perform lead optimization and candidate drug dose schedule exploration and to predict high vs. low incidence drug induced clinical diarrhea will be discussed.