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Cardiac safety of lacosamide: the non‐clinical perspective
Author(s) -
Delaunois A.,
Colomar A.,
Depelchin B. O.,
Cornet M.
Publication year - 2015
Publication title -
acta neurologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.967
H-Index - 95
eISSN - 1600-0404
pISSN - 0001-6314
DOI - 10.1111/ane.12413
Subject(s) - lacosamide , sodium channel , pharmacology , herg , qt interval , medicine , anesthesia , epilepsy , chemistry , sodium , potassium channel , organic chemistry , psychiatry
Objectives Lacosamide is indicated for the adjunctive treatment of partial‐onset seizures in adult patients. Unlike other sodium channel‐blocking antiepileptic drugs, lacosamide selectively enhances sodium channel slow inactivation. Potential effects of lacosamide on cardiac sodium channels and their cardiovascular consequences were comprehensively assessed. This manuscript presents the non‐clinical cardiac safety profile of lacosamide. Methods Lacosamide was tested in vitro on sodium and L‐type calcium currents from isolated human atrial myocytes and on hERG ‐mediated potassium currents from stably transfected HEK 293 cells. Cardiac action potentials were recorded in guinea pig ventricular myocytes. In vivo, hemodynamic and ECG parameters were evaluated in anesthetized dogs and monkeys receiving acute cumulative intravenous doses of lacosamide. Results Following intravenous dosing with lacosamide, dose‐dependent PR and QRS prolongation and ECG abnormalities (loss of P waves, atrioventricular and intraventricular blocks, junctional premature contractions) were observed in anesthetized dogs and monkeys. In vitro , lacosamide reduced human cardiac sodium currents in a concentration‐, voltage‐ and state‐dependent manner. Lacosamide reductions in V max in guinea pig myocytes were similar to lamotrigine and carbamazepine. Lacosamide showed no relevant inhibitory effects on hERG and L‐type calcium channels and did not prolong QT c in vivo . Conclusions ECG findings in anesthetized animals correlate well with in vitro sodium channel‐related effects and are also consistent with those ( PR prolongation, first‐degree atrioventricular block) reported in healthy volunteers and patients with epilepsy. Both in vivo and in vitro effects were detected from exposure levels 1.5‐ to 2‐fold above those achieved with the maximum‐recommended human lacosamide dose (400 mg/day).