Translational potential of a mouse in-vitro bioassay in predicting gastrointestinal adverse drug reactions in phase 1 clinical trials

Background: Motility-related gastrointestinal adverse drug reactions (GADRs) such as diarrhoea and constipation are a common and deleterious feature associated with drug development. Novel biomarkers of GI function are therefore required to aid decision making on the gastrointestinal liability of compounds in development. Methods: Fifteen compounds associated with or without clinical GADRs were used to assess the ability of an in vitro colonic motility bioassay to predict motility-related GADRs. Compounds were examined in a blinded fashion for their effects on mouse colonic peristaltic motor complexes in vitro. For each compound concentration-response relationships were determined and the results compared to clinical data. Compounds were also assessed using gastrointestinal transit measurements obtained using an in vivo rat charcoal meal model. Key Results: Within a clinically relevant dosing range, the in vitro assay identified 5 true and 3 false positives, 4 true and 3 false negatives, which gave a predictive capacity of 60%. The in vivo assay detected 4 true and 4 false positives, 4 false and 3 true negatives, giving rise to a predictive capacity for this model of 47%. Conclusion & Inferences: Overall these results imply that both assays are poor predictors of GADRs. Further analysis would benefit from a larger compound set, but the data shows a clear need for improved models for use in safety pharmacology assessment of GI motility