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Inhibitory Effects of Cenobamate on Multiple Human Cardiac Ion Channels and Possible Arrhythmogenic Consequences
Andreea Larisa Mateias,
Florian Armasescu,
Bogdan Amuzescu,
Alexandru Dan Corlan,
Beatrice Mihaela Radu,
:-, 2024
ABSTRACT
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: GABAA
receptors (EC50 42-194 µM) and persistent neuronal Na+ currents (IC50
59 µM). Side effects include QTc 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 (INa), hCav1.2 (α1c + β2 + α2δ1) (ICaL), hKv7.1 + minK (IKs),
and hKv11.1 (hERG) (IKr). We found IC50 of 87.6 µM (peak INa), 46.5 µM
(late INa), and 509.75 µM (ICaL). 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 INa 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.
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