Abstracts

Rationale: Preclinical and clinical data demonstrate that the synaptic vesicle protein 2A (SV2A) ligand levetiracetam (LEV) slowly distributes into brain tissues. This finding is due to its physicochemical properties and, possibly, active efflux by P-glycoproteins. When compared with LEV, brivaracetam (BRV) has a more favorable lipophilicity degree, higher in vitro and in vivo cell membrane permeability, and no interaction with efflux transporters. This study compared onset of action of BRV versus LEV in an animal model of epilepsy and predicted their permeability in human brain, in order to assess if fast brain uptake of BRV shows a promising therapeutic potential for acute treatment of prolonged and life-threatening seizures.Methods: Brain and plasma concentrations were measured at various post-dosing times after single oral dosing to audiogenic mice (0.82 mg/kg BRV and 6.5 mg/kg LEV) and to Beagle dogs (54 mg/kg LEV). Brain, cerebrospinal fluid, and blood samples were obtained in male Sprague-Dawley rats following single intravenous (IV) dosing (0.82 mg/kg BRV and 6.5 mg/kg LEV). A physiologically-based pharmacokinetic (PBPK) model was built assuming that only free molecules cross the blood-brain barrier following a first-order process. The model was used to determine the blood-brain barrier permeability (PS) of LEV and BRV across species, including humans. Pharmacokinetic parameters, predicted PS, in vitro binding constants, and plasma protein binding values were combined to estimate the time-course of SV2A occupancy in human subjects after standard IV doses of LEV (1500 mg) and BRV (100 mg).Results: In audiogenic mice, total brain-to-plasma ratio reached equilibrium more rapidly with BRV than with LEV, which translated into a faster onset of action. Through PBPK modeling, the predicted blood-brain barrier permeability in humans was assessed to be 23-fold higher for BRV when compared with LEV. After IV administration of recommended doses to patients, SV2A occupancy in the brain was predicted to be beyond 80% within 15 minutes with BRV, and 3 hours for LEV.Conclusions: When compared with LEV, BRV has higher brain permeability and no risk of active efflux transport. In animal models of epilepsy (audiogenic mice), the above properties turn into a faster onset of action. PBPK modeling predicts that this advantage extends to patients and highlights a promising therapeutic potential of BRV for acute intervention against status epilepticus or cluster seizures. UCB-sponsored