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Cardiac safety of lacosamide: the non-clinical perspective.

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Title: Cardiac safety of lacosamide: the non-clinical perspective.
Authors: Delaunois, A., Colomar, A., Depelchin, B. O., Cornet, M.
Source: Acta Neurologica Scandinavica. Nov2015, Vol. 132 Issue 5, p337-345. 9p.
Subjects: Cardiac surgery, Vimpat, Sodium channel blockers, Anticonvulsants, Cardiovascular diseases
Abstract: 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 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). [ABSTRACT FROM AUTHOR]
Copyright of Acta Neurologica Scandinavica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Cardiac safety of lacosamide: the non-clinical perspective.
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  Data: <searchLink fieldCode="AR" term="%22Delaunois%2C+A%2E%22">Delaunois, A.</searchLink><br /><searchLink fieldCode="AR" term="%22Colomar%2C+A%2E%22">Colomar, A.</searchLink><br /><searchLink fieldCode="AR" term="%22Depelchin%2C+B%2E+O%2E%22">Depelchin, B. O.</searchLink><br /><searchLink fieldCode="AR" term="%22Cornet%2C+M%2E%22">Cornet, M.</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Acta+Neurologica+Scandinavica%22">Acta Neurologica Scandinavica</searchLink>. Nov2015, Vol. 132 Issue 5, p337-345. 9p.
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  Data: <searchLink fieldCode="DE" term="%22Cardiac+surgery%22">Cardiac surgery</searchLink><br /><searchLink fieldCode="DE" term="%22Vimpat%22">Vimpat</searchLink><br /><searchLink fieldCode="DE" term="%22Sodium+channel+blockers%22">Sodium channel blockers</searchLink><br /><searchLink fieldCode="DE" term="%22Anticonvulsants%22">Anticonvulsants</searchLink><br /><searchLink fieldCode="DE" term="%22Cardiovascular+diseases%22">Cardiovascular diseases</searchLink>
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  Data: 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 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). [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Acta Neurologica Scandinavica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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