At the annual Safety Pharmacology Society (SPS) meeting in Montreal September, the results of a collaborative study between Actual Analytics Ltd, AstraZeneca, Charles River Laboratories, GSK, Johnson & Johnson and NC3Rs (UK) were presented by Dr Ajeesh Cherian (GSK).
The aim of the collaborative work was to assess the potential of rodent home cage monitoring, using a few key parameters (activity, rearing and body temperature), to predict risk over traditional FOB/Irwin tests. Three compounds (from GSK, JnJ and AZ), for which findings have previously been reported in FOB/Irwin and clinically (GSK and AZ), were tested using the home cage monitoring system.
Excitingly, all three compounds showed behavioural effects in the HCA systems some at concentrations not observed in FOB/Irwin. Further, many effects were seen during the dark phase which is usually missed in traditional tests.
The Results of a Multi-Company Validation of the ActualHCATM Home Cage Monitoring System for Rodent CNS Safety Pharmacology Studies
Traditional core battery CNS safety pharmacology assessment relies on the FOB/Irwin, a subjective behavioural screen including a panoply of rodent-specific parameters that are sometimes difficult to translate to human outcomes. Home cage monitoring systems objectively measure continuous rodent behavior, day and night, over multiple days. The welfare benefits of the approach which allows group housing and non-invasive monitoring are established. However, how these data compare to those obtained in the FOB/Irwin remains largely untested.
The aim of this collaborative work was to assess the potential of rodent home cage monitoring using a few key parameters to predict risk over traditional FOB/Irwin, using preclinical and clinical data from three compounds for which adverse effects have previously been reported.
Body temperature and behavioral data (e.g. locomotion, rearing, drinking, social interactions) were collected in group-housed animals in the homecage to create a continuous behavioural profile which was then compared with findings from the original FOB/Irwin studies. All compounds exhibited behavioural responses compared to controls with initial responses broadly in line with expected effects. However night-time effects, not measured in the original studies were very clearly visible. For two compounds the initial response was a pronounced hyperactivity measured via distance moved and rearing with parallel increase in body temperature which was then followed by a generally suppressed hypoactive phase at the end of the dose day. The hypoactivity effect was strongly dose-dependent and unexpectedly then extended across multiple days, after a single treatment. More subtle changes in drinking and social interactivity were also observed across the treatment groups.
The continuous behavioural profile obtained from the homecage monitoring graphically demonstrated the inherent behavioural variability in animals over time and clearly highlighted the sampling risk in using snapshot observations of behaviour at arbitrary times. The continuous profiles unmasked effects that were not originally detected likely due to the FOB/Irwin sampling times, or detected to a lesser extent and thus not initially flagged as relevant. Home cage monitoring represents an animal welfare refinement and could be used in repeat dose toxicology studies alongside clinical observations in place of FOB/Irwin.