Lacosamide for the prevention of partial onset seizures in epileptic adults

Abstract

Lacosamide is a newly registered antiepileptic drug with dual mechanisms of action. It selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. It also binds to a collapsing-response mediator protein-2, CRMP2. Lacosamide has a favorable pharmacokinetic profile; is rapidly and completely absorbed, has a relatively long elimination half-life of 13 hours which allows twice-daily administration, linear pharmacokinetics, and has low potential for drug interactions and renal elimination. Both oral and intravenous formulations of lacosamide are being developed. In placebo-controlled clinical trials, lacosamide was effective in seizure reduction as adjunctive therapy in patients with uncontrolled partial-onset seizures. Lacosamide was generally well tolerated. The most frequently reported adverse events in placebo-controlled trials were dizziness, headache, nausea, and diplopia. Intravenous lacosamide has a comparably good safety profile.

Keywords: epilepsy; lacosamide; partial onset seizures.

Figure 1

Working modes of voltage-gated sodium channels. At the resting potential, sodium channels are closed and can be opened by depolarization of the membrane potential which allow the flux of sodium ions into the cell. The channels close within a few milliseconds from inside of the neuron and go into a fast inactivated state from which they cannot be reactivated. W hen the membrane potential returns to baseline, the sodium channel goes back to its resting state. Under conditions of slight prolonged depolarization and repetitive neuronal activity, the sodium channel can go into a slow inactivated state by closing the pore from inside. This process happens on a second-to-minute time scale. Drugs can either block the open channel (eg, local anesthetics), or enhance fast inactivation (classical anticonvulsants), or enhance slow inactivation (lacosamide). Copyright © 2007. John Wiley and Sons. Reproduced with permission from Beyreuther B, Freitag J, Heers C, Krebsfänger N, Scharfenecker U, Stöhr T. Lacosamide: a review of preclinical properties. CNS Drug Rev. 2007;13:21–42.

Figure 2

Percentage of patients with at least 50% or 75% reduction in seizure frequency from baseline period to the maintenance period. Pooled efficacy data of SP667, SP754, and SP755 trials. Notes: *P < 0.05, **P < 0.001 vs placebo. Inferential statistics for the 75% responders are not available. Copyright © 2009 Expert Reviews Ltd. Reproduced with permission from Beydoun A, D'Souza J, Hebert D, Doty P. Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures. Expert Rev Neurother. 2009;9(1):33–42. Abbreviation: LCM, lacosamide.

Figure 3

Median percentage reduction in seizure frequency per 28 days from the baseline period to the maintenance period. Pooled efficacy data of SP667, SP754, and SP755 trials. Notes: *P < 0.05, **P < 0.001 vs placebo. Inferential statistics for the 75% responders are not available. Copyright © 2009. Reproduced with permission from Beydoun A, D'Souza J, Hebert D, Doty P. Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures. Expert Rev Neurother. 2009;9(1):33–42. Abbreviation: LCM, lacosamide.