Seizure Liability and Premonitory Sign Incidence: Opportunities and Pitfalls with Standalone EEG Studies or When EEG is Included in Repeat Dose Toxicology (S04-1)

Even when a seizure liability is present, the incidence is typically highly variable and the onset of neurotoxicological effects can require prolonged exposure which renders standalone seizure liability studies challenging from a resource and ethical standpoint. The inclusion of safety pharmacology endpoints with telemetry devices in repeat dose toxicology typically raises concerns related to general toxicology data interpretation and potential confounding effects. Correlating in-vivo neurological signs with parent and metabolite exposure profile is required in repeat dose toxicology but also in seizure assessments offering potential synergistic designs. This presentation will review and discuss important considerations related to the seizure liability characterization when including EEG in repeat dose toxicology studies in comparison to standalone studies. Approaches relevant to animal species commonly used in toxicology such as Beagle dogs, rats, non-human primates and minipigs will be evaluated. Lastly, translational considerations and regulatory approaches to EEG biomarkers of seizure risk will be discussed.