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Neurogastroenterol Motil. 2014 Jul;26(7):980-9. doi: 10.1111/nmo.12349. Epub 2014 May 11.

Translational potential of a mouse in vitro bioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials.

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1
Department of Biomedical Sciences, University of Sheffield, Sheffield, UK.

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.

KEYWORDS:

adverse drug reaction; bioassay; biomarker; gastrointestinal motility; safety pharmacology

PMID:
24813024
PMCID:
PMC4207192
DOI:
10.1111/nmo.12349
[Indexed for MEDLINE]
Free PMC Article
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