Objective:

Characterize cenobamate’s mechanism of action (MOA) based on currently available evidence.

Background:

In phase 2 trials, cenobamate demonstrated a robust antiseizure effect in patients with difficult-to-treat focal seizures, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic. 

Design/Methods:

We review the available evidence and provide further insight on cenobamate’s MOA. 

Results:

Preclinical studies showed that cenobamate exerts effects on voltage-gated sodium channels (NaV) and GABA_A receptors. The I_NaP contributes to the generation of a paroxysmal depolarization shift, which may serve as a basis for epileptic foci. There is an increase in I_NaP in spontaneously bursting hippocampal neurons after epileptogenic stimuli such as experimental status epilepticus. In preclinical studies, cenobamate modulated NaV by preferential blockade of the I_NaP, while sparing the transient sodium current (I_NaT). It is likely that by sparing the I_NaT, cenobamate does not interfere with fast-spiking GABAergic interneuron function, thus preserving network inhibition. The effect of cenobamate’s selective I_NaP block on the resting membrane potential is augmented by its positive allosteric modulation of GABA_A receptor-mediated tonic currents. This effect was not reversed by flumazenil and cenobamate did not displace flunitrazepam binding, which suggests positive allosteric GABA_A modulation via non-benzodiazepine binding sites. The combined effects of limiting I_NaP while augmenting tonic GABA-mediated chloride currents effectively suppress the epileptiform activity of principal neurons. Cenobamate’s selectivity for the I_NaP over I_NaT likely represents action on the NaV1.6 channel over the NaV1.1 channel and is a feature not shared by traditional antiseizure medications like phenytoin or carbamazepine.

Conclusions:

Cenobamate selectively inhibits I_NaP, which may involve preferential action at NaV1.6 over NaV1.1 channels, while sparing I_NaT. Sparing the I_NaT is critical for preserving the inhibitory activity of fast-spiking interneurons. This effect on I_NaP may be enhanced by cenobamate’s positive allosteric modulation of tonic (extrasynaptic) GABA_A receptors.