Inhibitory Effects of Cenobamate on Multiple Human Cardiac Ion Channels and Possible Arrhythmogenic Consequences

Cenobamate is a novel third-generation antiepileptic drug used for the treatment of focal onset seizures and particularly for multi-drug-resistant epilepsy; it acts on multiple targets: GABA_A receptors (EC₅₀ 42-194 µM) and persistent neuronal Na⁺ currents (IC₅₀ 59 µM). Side effects include QT_c interval shortening with >20 ms, but not <300 ms. Our in vitro cardiac safety pharmacology study was performed via whole-cell patch-clamp on HEK293T cells with persistent/inducible expression of human cardiac ion channel isoforms hNav1.5 (<i>I</i>_Na), hCav1.2 (α1c + β2 + α2δ1) (<i>I</i>_CaL), hKv7.1 + minK (<i>I</i>_Ks), and hKv11.1 (hERG) (<i>I</i>_Kr). We found IC50 of 87.6 µM (peak <i>I</i>_Na), 46.5 µM (late <i>I</i>_Na), and 509.75 µM (<i>I</i>_CaL). In experiments on Ncyte^® ventricular cardiomyocytes, APD90 was reduced with 28.6 ± 13.5% (mean ± SD) by cenobamate 200 µM. Cenobamate's marked inhibition of <i>I</i>_Na raises the theoretical possibility of cardiac arrhythmia induction at therapeutic concentrations in the context of preexisting myocardial pathology, in the presence of action potential conduction and repolarization heterogeneity. This hypothetical mechanism is consistent with the known effects of class Ib antiarrhythmics. In simulations with a linear strand of 50 cardiomyocytes with variable inter-myocyte conductance based on a modified O'Hara-Rudy model, we found a negligible cenobamate-induced conduction delay in normal tissue, but a marked delay and also a block when gap junction conduction was already depressed.