Brivaracetam or levetiracetam in status epilepticus?: Lessons from the photosensitivity model

Abstract

First, a short history is given of the use of the EEG as a biomarker of efficacy in anti-seizure medication (ASM) development. The generalized epileptiform EEG response to Intermittent Photic Stimulation (IPS), the photoparoxysmal EEG response or PPR, in particular, is a reliable reproducible measure since the 1950s. Over time, a "Photosensitivity Model", testing within the same patients the impact of potential new oral ASMs, along with dose-ranging data, on PPRs, has been developed successfully. The classical Photosensitivity Model consists of IPS and blood sampling for ASM measurement performed hourly between 8 AM and 5 PM over three consecutive days. This single-blind, placebo-controlled, pharmacokinetic-pharmacodynamic (PK/PD) Model is now commonly utilized as a Proof-of-Concept Phase 2a trial. For Generalized Tonic-Clonic Status Epilepticus (GTCSE), it is especially relevant to know the time for CNS entry and effect minutes after i.v. ASM treatment, since "time is brain". We, therefore, adapted successfully the Model to a time-efficient Model with the determination of photosensitivity ranges in minutes after equivalent doses of iv brivaracetam (BRV) and levetiracetam (LEV). This modified design allows one to monitor the time to CNS effect (i.e., PPR elimination) of a quickly-acting FDA-approved ASM given i.v., a crucial element in status epilepticus treatment. This paper was presented at the 8th London-Innsbruck Colloqium on Status Epilepticus and Acute Seizures held in September 2022.

Keywords: ASM efficacy; Adaptation of the Model; EEG; PK/PD; Photosensitivity; Time to CNS effect.