Translational potential of a mousein vitrobioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials

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Abstract

Background

Motility-related gastrointestinal (GI) adverse drug reactions (GADRs) such as diarrhea 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 GI 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 GI transit measurements obtained using an in vivo rat charcoal meal model.

Key Results

Within a clinically relevant dosing range, the in vitro assay identified five true and three false positives, four true and three false negatives, which gave a predictive capacity of 60%. The in vivo assay detected four true and four false positives, four false and three true negatives, giving rise to a predictive capacity for this model of 47%.

Conclusions & 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 show a clear need for improved models for use in safety pharmacology assessment of GI motility.

Conclusions & Inferences

Bioassays that are capable of quantifying gastrointestinal adverse drug reactions (GADRs) such as diarrhea or constipation are required to aid safety pharmacology screens. This study investigates the translational potential of an in vitro motility bioassay to predict motility-related GADRs and discusses the results in terms of safety pharmacology screening systems.

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