Inhibitory effects of cenobamate on multiple human cardiac ion
  channels and possible arrhythmogenic consequences

Bogdan Amuzescu; Alexandru Dan Corlan; Beatrice  Radu

Inhibitory effects of cenobamate on multiple human cardiac ion channels and possible arrhythmogenic consequences

Bogdan Amuzescu, Alexandru Dan Corlan, Beatrice Radu,

:-, 2023

ABSTRACT

Cenobamate is a novel third-generation antiepileptic drug used for treatment of focal onset seizures and particularly for multi-drug-resistant epilepsy, producing a reduction in monthly seizure frequency of up to 55% and unprecedented seizure-free rates of up to 28% due to action on multiple targets: GABA A receptors (EC50 42–194µM) and inhibition of persistent neuronal Na ⁺ currents (IC50 59µM). Side effects include QT c interval shortening with > 20ms, but not < 300ms; therefore, cenobamate is forbidden for patients with short QT syndrome. 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 Na ), hCav1.2 (α1c + β2 + α2δ1) ( I CaL ), hKv7.1 + mink ( I Ks ), and hKv11.1 (hERG) ( I Kr ), using specific bath/pipette solutions and voltage protocols. Thus, we succeeded to evidence for exposure to cenobamate 200µM average inhibitions (± SD) of 69.5 ± 14.6% for peak I Na , 39.3 ± 13.8% for peak I CaL (which may explain QT shortening effects), 36.7 ± 13.0% vs . 23.7 ± 9.9% in control experiments for I Ks , 5.3 ± 1.8% vs . 4.1% in control experiments for I Kr (at 20µM). The marked inhibition by cenobamate of I Na raises the theoretical possibility of cardiac arrhythmia induction at therapeutic concentrations in the context of preexisting myocardial pathology, in the presence of electrophysiological conduction and repolarization heterogeneity. This hypothetical mechanism is consistent with known effects of class Ib antiarrhythmics. In preliminary simulations with linear cardiomyocyte strands we found a negligible cenobamate-induced conduction delay in normal tissue, but a marked delay and also block when gap junction conduction was already depressed.

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