Abstracts

Rationale: The Maximal Electroshock Seizure (MES) assay has been widely used to characterize the efficacy of antiepileptic drugs, including those used in the treatment of focal seizures via sodium channel (Na_V) inhibition.    Although the dose-dependence of activity of such Na_V inhibitors has been well defined, the relationship between plasma and brain concentration and efficacy is not often assessed. Here, we report the plasma and brain EC₅₀’s in the mouse MES assay and compare them with plasma concentrations observed at effective clinical exposures in patients.  XEN901 is the first selective inhibitor of Na_V1.6 to enter clinical development, and we predict that XEN901 may be more effective than non-selective Na_V inhibitors as it does not block Na_V1.1 in inhibitory GABAergic interneurons. Block of Na_V1.1 should be proconvulsant, as heterozygous loss-of-function mutations in Na_V1.1 cause Dravet Syndrome, a severe infantile epilepsy.  The correlation between plasma concentration needed for efficacy in the MES assay and in therapeutic use in patients, allows a potential prediction of the effective plasma concentration of XEN901 required for human therapeutic use. Methods: The MES assay was conducted with CF1 mice using protocols and mice strains that closely follow those used in the NINDS Epilepsy Therapy Screening Program (ETSP).  All Na_V inhibitors tested were dosed once by gavage. Plasma samples were taken from mice used in these studies at the end of experiments, typically about 2.5 hours after dosing.  Results: Concentration-response curves describing the inhibition of tonic seizures were well described by a 1:1 binding reaction.  The EC₅₀ for phenytoin, carbamazepine, lacosamide and XEN901 were 4.4, 12.0, 5.3 and 0.12 µM, respectively.  For phenytoin, carbamazepine and lacosamide, these compared to human clinical exposures of 12-120 µM, 17-51 µM and 20-60 µM, respectively. Conclusions: For the Na_V channel inhibitors phenytoin, carbamazepine and lacosamide, the plasma concentration needed for clinical efficacy is 1-5 times the plasma EC₅₀ in the mouse MES assay.  In other words, for efficacy in humans one needs to achieve plasma levels that are equivalent to or greater than the EC₅₀ for protection in the mouse MES assay.  In Phase I clinical trials, XEN901 is well tolerated at >20 times the EC₅₀ in the MES assay.  Thus, based on the MES assay, therapeutically effective concentrations of XEN901 may be achieved in humans with an enhanced therapeutic index.   Funding: None