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

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.

Toxicity testing in the 21st century beyond environmental chemicals

“…Several such data sets have been collected in the course of the IMI eTOX project, but they have not (yet) been made available for the public. More studies like this should be available to the scientific community ( Leist et al, 2014 ) to have new tools for comparing animal results with the effects in humans with the aim to better understand the relevance of the new techniques; to this effect it should be noted that some recent examples are emerging ( Ewart et al, 2014 ; Keating et al, 2014 ; Valentin et al, 2013 ). Moreover, this type of approach may help to distinguish between true side effects of the new drug and the unforeseen adverse event that derives from excess pharmacology.…”

Gastrointestinal Safety Pharmacology in Drug Discovery and Development

“…Taken together, differences in functional and molecular pathways controlling GI function between rodents and human potentially compromise the translational value of drug effects from laboratory animals to humans (Sanger et al 2011(Sanger et al , 2013. Therefore, there is a need to develop preclinical model(s) with better predictive value for early screening of GI motility liability of novel compounds in development (Keating et al 2014). …”

“…In a recent study, Keating et al (2014) assessed the predictive potential of in vitro and in vivo rodent GI motility models by testing the effect of 15 compounds, including 8 compounds with known gastrointestinal adverse drug reactions (diarrhea or constipation). An in vitro mouse model measuring colonic peristaltic motor activity and the standard rodent charcoal meal GI transit model were found to be poor predictors of the expected motility changes associated with diarrhea or constipation observed in the clinic.…”

Principles of Safety Pharmacology

“…An in vitro mouse model measuring colonic peristaltic motor activity and the standard rodent charcoal meal GI transit model were found to be poor predictors of the expected motility changes associated with diarrhea or constipation observed in the clinic. Therefore, there is a need to develop preclinical model(s) with better predictive value for early screening of GI motility liability of novel compounds in development (Keating et al 2014). Therefore, there is a need to develop preclinical model(s) with better predictive value for early screening of GI motility liability of novel compounds in development (Keating et al 2014).…”