title: Cardiac safety of lacosamide: the non-clinical perspective.
abstract: OBJECTIVE
  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 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.
  
  
  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 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.
  
  
  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).
authors.affiliation: Non-Clinical Development, UCB Biopharma SPRL., Braine l'Alleud, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Delaunois
authors.affiliation: Non-Clinical Development, UCB Biopharma SPRL., Braine l'Alleud, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Colomar
authors.affiliation: Non-Clinical Development, UCB Biopharma SPRL., Braine l'Alleud, Belgium.
authors.forename: B O
authors.initials: BO
authors.lastname: Depelchin
authors.affiliation: Non-Clinical Development, UCB Biopharma SPRL., Braine l'Alleud, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Cornet
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects*; D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D066126:Cardiotoxicity; D002478:Cells, Cultured; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006168:Guinea Pigs; D057809:HEK293 Cells; D000882:Haplorhini; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D000078334:Lacosamide; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D051638:Ether-A-Go-Go Potassium Channels; D015222:Sodium Channels; D000078334:Lacosamide
keywords: PR interval, QRS complex; arrhythmia; cardiac sodium channels; lacosamide; preclinical cardiac safety