Predicting seizure liability of small molecules using an in vitro multi-electrode array based assay coupled with modeling of brain disposition

Abstract

Unintended central nervous system (CNS) effects of small molecule drugs can lead to costly attrition during drug development. CNS liability can be assessed with biochemical assays, as part of routine nonclinical toxicology studies, or via a battery of rodent CNS tests. Alternative in vitro methods have been developed for assessing CNS liability of small molecule drugs though their use in drug development has lagged relative to other organ systems of interest including cardiac, hepatic, and gastrointestinal. In the present study, 13 commercially available small molecule drugs and 15 experimental AbbVie compounds were evaluated in an in vitro seizure assay consisting of human-induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons cultured on a multi-electrode array (MEA). Across all 28 compounds, the in vitro seizure assay exhibited 58% sensitivity and 78% specificity. A mathematical model of brain penetrance was used to predict brain exposures in cynomolgus monkey and improved the concordance of the in vitro seizure assay with in vivo seizure liability, highlighting that the in vitro assay together with CNS exposure prediction could serve as a useful tool for characterizing seizure liability of a small molecule drug candidate.