In Vitro Human Ion Channel Assays Predictive of Drug Induced Seizure (S04-2)

Gaining a better mechanistic understanding of off-targets causative of seizure will improve identification of potential seizure risks of drugs pre-clinically. In the present study, we evaluated nine ion-channel targets with strong correlative links to seizure or convulsion. Each target was assessed using a human in vitro functional activity assay with a library of >60 preclinical compounds or approved drugs with known effects of convulsion in vivo but with unknown seizure mechanisms. Results showed that three of the targets had a high frequency of positive hits (IC30 ≤ 10 µM). The in vitro ion-channel IC30 concentration correlated well with the in vivo peripheral Cmax (free) across the compound library, with a sensitivity of 71% and specificity of 67% for the preclinical compounds. Expanded testing is ongoing to confirm sensitivity and specificity of the targets.