The Cardiac Sodium Channel Safety Profile of Cenobamate at Therapeutic Concentrations: In Vitro Analyses

The US Food and Drug Administration (FDA) issued a Drug Safety Communication for the antiseizure drug lamotrigine (Lamictal), warning of the risk of QRS prolongation and cardiac arrhythmias. The FDA also requested that other antiseizure medications with a similar mechanism of action (e.g., block of neuronal sodium channels), including cenobamate, be evaluated for their risk as a cardiac sodium channel blocker. The purpose of this in vitro study was to determine the cardiac sodium channel blocking effects of cenobamate and its sodium channel classification. Follow-up experiments were also performed with cenobamate at its highest free therapeutic concentration (66 μM). Experiments were performed using the manual patch clamp technique at physiologic temperatures. Despite its classification as a Class Ib and Id antiarrhythmic, cenobamate was found to have little effect on the cardiac sodium channel when tested in vitro at therapeutic levels. These findings provide further clarity and support for the clinical safety of cenobamate in patients without cardiovascular risk factors.