Figure 2.

Translating SV2A and GABA_A receptor target engagement from rodents to humans. In the amygdala kindling model of chronic epilepsy, the ED₅₀, the PSL dose that protected 50% of mice against focal-to-bilateral seizures was 1.2 mg/kg. In vivo occupancy studies in mice showed that at this dose, PSL exhibited >90% SV2A occupancy and ∼10% occupancy at GABA_A receptors (GABA_ARs). The differential proportionality of target engagement was retained in humans as shown in PET studies following administration of PSL 400 mg bid; >90% SV2A and 13% GABA_AR occupancy. SV2A occupancy was sustained; in contrast, GABA_AR occupancy was transient, and at 2 h post-dose, occupancy for the average of all regions of interest was ≤5% for most volunteers. The 400 mg bid dose was selected for the Phase II proof-of-concept trial, as it was expected to achieve exposure levels similar to those associated with robust efficacy in the amygdala kindling model; high, sustained SV2A, and low, transient GABA_AR occupancy.