lacosamide and Cardiotoxicity

To determine whether lacosamide prolongs the corrected QT interval (QTc).. In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability.. The QTcI mean maximum difference from placebo was -4.3 ms and -6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin (-0.5 and -2.5 ms, respectively). Placebo-corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose-related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems.. Lacosamide (≤ 800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, dose-related increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures.

Topics: Acetamides; Adult; Anticonvulsants; Cardiotoxicity; Double-Blind Method; Electrocardiography; Female; Healthy Volunteers; Heart Rate; Humans; Lacosamide; Male; Middle Aged

Lacosamide is a third-generation antiepileptic drug. Its likely mechanism of action is via neuronal sodium channel blockade, via a unique manner compared with other antiepileptic drugs that block sodium channels. A paucity of information exists regarding lacosamide overdosage. Lacosamide overdosage is thought to cause QRS prolongation and seizures, due to its effect of sodium channel blockade. The potential efficacy of sodium bicarbonate to reverse the effects of lacosamide has not been well studied. Furthermore, prior reports of lacosamide toxicity have occurred in the setting of concomitant polypharmacy. Thus, the isolated toxic effects of the drug have not been well elucidated.. We report a case of a suspected, single-ingestion overdose on lacosamide. The patient developed signs of cardiotoxicity and seizure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: After lacosamide overdosage, the emergency physician must be capable of acute management of subsequent lacosamide toxicity. Understanding the mechanisms of action causing toxicity due to this drug can help the clinician to anticipate the interventions that may be needed or useful to treat this potentially toxic ingestion.

Topics: Arrhythmias, Cardiac; Cardiotoxicity; Drug Overdose; Electrocardiography; Epilepsy; Female; Humans; Lacosamide; Middle Aged; Seizures; Sodium Bicarbonate

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.. 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 HEK293 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.. 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 Vmax 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 QTc in vivo.. 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).

Topics: Acetamides; Action Potentials; Adult; Animals; Anticonvulsants; Cardiotoxicity; Cells, Cultured; Dogs; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Haplorhini; Heart Rate; HEK293 Cells; Humans; Lacosamide; Sodium Channels