Abstract
ABSTRACT
Central nervous system (CNS) liabilities remain a significant cause of attrition during small molecule drug development. We previously developed the in vitro seizure liability assay (iLA
seizure
), a new approach methodology (NAM) comprising a human induced pluripotent stem cell neuron microelectrode array (MEA) assay coupled with a panel of human ion channels associated with CNS perturbation and especially seizure, evaluated by electrophysiology. Here, we present a series of illustrative case studies demonstrating the potential applications of iLA
seizure
. Amoxapine (shows clinical seizures) gave concentration‐dependent changes in MEA parameters and inhibited seizure‐related ion channels with high potency (IC
50
50
of 19.3 μM). In the third case study, one clinical candidate showed no changes in MEA parameters at the clinical C
max
of 1 μM, whereas the other clinical candidate showed a potent seizurogenic phenotype with changes in many MEA parameters at 3–10 μM, correlating with the clinical C
max
of 5 μM. Overall, iLA
seizure
offers new opportunities to predict, understand, and avoid CNS side effects such as seizures in drug discovery and development, before animals, resources, and time have been wasted. This work should be considered within the context of recent proposed updates to safety pharmacology guidelines, such as ICH S7A. However, further work is needed to validate assay performance and clarify the context of use.