University of Hertfordshire

From the same journal

By the same authors

Documents

  • 907056

    Final published version, 565 KB, PDF document

View graph of relations
Original languageEnglish
Pages (from-to)980-9
JournalNeurogastroenterology and Motility
Volume26
Issue7
Early online date11 May 2014
DOIs
Publication statusPublished - Jul 2014

Abstract

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

Notes

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

ID: 2076871