Aim and impact of the project

Objective: To obtain the in vitro drug safety profile of the two-newly approved antiepileptics

The most significant scientific results obtained in the EPISAFE project are the following:

1. CBM, at clinically relevant concentrations, has significant inhibitory effects on voltage-dependent cardiac ion channels: Na+ channels (Nav1.5) and L-type Ca2+ channels (Cav1.2)

2. CBM has a shortening effect on the duration of the ventricular action potential in our experimental (including human induced pluripotent stem cell-derived cardiomyocyte experiments) and simulation studies, confirming the QT shortening effects described in previous clinical and non-clinical studies

3. Highlighting through simulation studies the consequences of the inhibitory effects of CBM on the propagation of the action potential at the ventricular level and the possibility of the appearance of some re-entry circuits in areas of pathological myocardium, with altered coupling conductance between myocytes (for example ischemic foci, sequelae of infarction myocardial, areas of fibrosis, etc.) that can trigger dangerous, potentially lethal ventricular arrhythmias

4. Study by molecular modeling methods of the interaction of CBM with human Na+ channels Nav1.5, description of the binding site in the central cavity of the channels and residues with which the drug interacts, estimation of the interaction free energy (ΔG) cenobamate-Nav1. 5 and the dissociation constant (Kd) for the wild-type canonical variant (UniProt sequence Q14524-1) and 8 point mutants of some residues in the binding site area by docking and molecular dynamics followed by MM-GBSA/MM-PBSA analysis, highlighting 3 point mutants: N1462L/Y (rs1064795922, rs199473614) and M1765R (rs752476527) having higher affinity than the wild-type variant (of the order 30 µM versus 90 µM).

The impact of these findings for medical practice is significant, given the expected widespread use of CBM in adult recurrent focal epilepsies and epilepsy resistant to other drugs. Thus, the study results in the need for careful cardiological monitoring of patients with structural myocardial defects, especially during the period of establishment of CBM treatment and dose determination. The administration of CBM is also contraindicated in patients presenting the mentioned point mutant variants.