Abstracts

Rationale: Positron emission tomography (PET) imaging provides quantitative information regarding target density and target occupancy by a drug in the brain. Levetiracetam (LEV) is an antiepileptic drug that binds to synaptic vesicle glycoprotein 2A (SV2A). Preclinical data suggest that brivaracetam (BRV) - an SV2A antiepileptic drug in Phase III development - has higher brain permeability than LEV. In rodent epilepsy models, full seizure protection with LEV occurs 30 min after peak plasma concentration, while BRV confers seizure protection almost immediately. To evaluate whether PET imaging could be used to measure the difference in brain entry rates between LEV and BRV in humans, we conducted a pilot study using SV2A PET imaging in rhesus monkeys. Methods: Using the new SV2A PET tracer [¹¹C]UCB-J, 4 displacement experiments were performed in 2 rhesus monkeys to estimate the time-course of tracer exit from the brain after intravenous (IV) administration of BRV (5mg/kg) or LEV (30mg/kg). Time-activity curves from all brain regions for each experiment were used to estimate the tracer displacement halftime for BRV and LEV. This halftime is defined as the time it takes from IV administration of a drug until half of maximal tracer displacement has occurred. These halftimes were then used to estimate brain entry rates of BRV and LEV. Results: The estimated tracer displacement halftime was 7 min for BRV and 35 min for LEV. This demonstrates that in non-human primates, BRV enters the brain faster than LEV. Since the halftime of tracer displacement is determined by the entry of a drug into the brain and by the clearance of the tracer from the brain, tracer displacement halftimes overestimate the time it actually takes for a drug to enter the brain. By correcting for the halftime of tracer clearance, the speed of brain entry of BRV and LEV can be estimated. The corrected halftimes were approximately 1 min for BRV and 28 min for LEV. Conclusions: PET data in rhesus monkeys confirmed the fast brain entry of BRV, which is consistent with rodent efficacy data. It also shows that PET imaging may be used to assess the difference rate of brain entry between BRV and LEV in humans. If this difference exists in humans, it means that BRV's anti-seizure efficacy may occur within minutes of IV administration (similar to benzodiazepines) while LEV's anti-seizure efficacy would not occur until 30 minutes or more after IV administration. The potential clinical benefit of this in acute seizures remains to be demonstrated. UCB supported