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

C Keating,J.P Valentin,L Grundy,L Ewart,D Grundy

doi:10.1111/nmo.12349

Abstract

BackgroundMotility-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.MethodsFifteen 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 ResultsWithin 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 & InferencesOverall 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.

Highlights

Gastrointestinal adverse drug reactions (GADRs) represent around 67% of adverse drug reactions (ADRs) described on drug labels[1] and account for 23% of adverse events encountered in phase I studies.[2]
Eight of the compounds caused diarrhea or constipation affecting between 17% and 100% of the patients, while seven had no reported GADRs such as diarrhea or constipation one, rimonabant (Compound S), was reported to cause nausea (Table 1)
The actions of the test compounds upon colonic peristaltic motor complexes (CPMCs) amplitude and time in quiescence (TIQ) were plotted as percentage changes relative to the vehicle response and were compared to appropriate time-matched controls (Fig. 3)

Summary

Introduction

Gastrointestinal adverse drug reactions (GADRs) represent around 67% of adverse drug reactions (ADRs) described on drug labels[1] and account for 23% of adverse events encountered in phase I studies.[2] Motility-related GADRs such as diarrhea and constipation are common side-effect profiles of marketed drugs,[3,4,5,6] and account for a high proportion of ADRs encountered during the development of new chemical entities.[7] Gastrointestinal adverse drug reactions can be dose limiting preclinically and/or clinically, affect patient compliance, or even lead to compound discontinuation.[8] GADRs pose a genuine clinical issue and are contributing to the escalating costs of developing new drugs.[9,10] Accurate and simple biomarkers of gastrointestinal (GI) function are required to detect potential GADRs earlier in the drug discovery pathway and so maximize the opportunity to ‘design out’ this undesirable characteristic, or to deselect compounds from on-going development. Novel biomarkers of GI function are required to aid decision making on the GI liability of compounds in development

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Results

Discussion

Conclusion