Key result
Cenobamate at 200 µM produced an average inhibition of 69.5% for peak INa and 39.3% for peak ICaL, explaining its QTc shortening effects and potential arrhythmogenic consequences in pathological myocardium.
Why the study?
Cenobamate causes QTc interval shortening and is contraindicated in short QT syndrome, prompting evaluation of its cardiac safety and effects on cardiac ion channels.
Cenobamate inhibits multiple human cardiac ion channels in vitro, particularly sodium and calcium channels, providing a potential mechanism for its known QT-shortening effects and raising theoretical proarrhythmic concerns in diseased myocardium.
QTc shortening with cenobamate may warrant ECG monitoring in epilepsy patients; leaves open arrhythmic implications in those with cardiac conduction disease.
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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Amuzescu et al. (2023) studied Cardiac ion channel electrophysiology. Cenobamate vs. Control (DMSO solvent) was evaluated on Inhibition of peak INa (hNav1.5). Cenobamate at 200 µM produced an average inhibition of 69.5% for peak INa and 39.3% for peak ICaL, explaining its QTc shortening effects and potential arrhythmogenic consequences in pathological myocardium.
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