Abstracts

Rationale: One of the potential mechanisms of AED resistance is the limitation of AED penetration into epileptogenic brain regions due to over-expression of efflux transporters such as P-glycoprotein (P-gp; also known as MDR1) at the blood-brain-barrier. Padsevonil (PSL; UCB0942) is a new AED candidate characterized by high affinity for the synaptic vesicle 2 proteins (SV2A, SV2B, SV2C) and moderate affinity for the benzodiazepine binding site on the GABA_A receptor. PSL is in clinical development for treatment of drug-resistant focal seizures. Using preclinical in vitro and in vivoapp). In the concentration equilibrium conditions, compounds were incubated in compartment A and B at the same concentration and samples were collected from both compartments. All experiments were performed in triplicate and quality controls for monolayer integrity and transporter expression were run in parallel. In vivoapp) with P_app value >300 nm/s in all cell lines and no evidence of being a P-gp substrate as demonstrated by nER values close to 1 (Table). In contrast to PSL, the desmethyl metabolite seems to be a P-gp substrate (Table). These findings were confirmed by the concentration equilibrium assay. In accordance with the in vitroin vivoin vivo