Translational potential of a mouse in vitro bioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials. Issue 7 (11th May 2014)

• Record Type: Journal Article
• Authors: Keating, C.; Ewart, L.; Grundy, L.; Valentin, J.P.; Grundy, D.
• Is Part Of: Neurogastroenterology & motility. Volume 26:Issue 7(2014:Jul.)
• Page Start: 980
• Page End: 989
• Publication Date: 2014-05-11
• Subjects: Gastrointestinal system -- Motility -- Periodicals; Gastrointestinal system -- Innervation -- Periodicals; 616.33
• DOI: 10.1111/nmo.12349
• Languages: English
• ISSNs: 1350-1925

Abstract

<abstract abstract-type="main" id="nmo12349-abs-0001"> <title>Abstract</title> <sec id="nmo12349-sec-0001" sec-type="section"> <title>Background</title> <p>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.</p> </sec> <sec id="nmo12349-sec-0002" sec-type="section"> <title>Methods</title> <p>Fifteen compounds associated with or without clinical GADRs were used to assess the ability of an <italic>in vitro</italic> colonic motility bioassay to predict motility‐related GADRs. Compounds were examined in a blinded fashion for their effects on mouse colonic peristaltic motor complexes <italic>in vitro</italic>. 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 <italic>in vivo</italic> rat charcoal meal model.</p> </sec> <sec id="nmo12349-sec-0003" sec-type="section"> <title>Key Results</title> <p>Within a clinically relevant dosing range, the <italic>in vitro</italic> assay identified five true and three false positives, four true and three false negatives, which gave a predictive capacity of 60%. The <italic>in vivo</italic> 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%.</p> </sec> <sec id="nmo12349-sec-0004" sec-type="section"> <title>Conclusions & Inferences</title> <p>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.</p> </sec> </abstract>