Lacosamide: Pharmacology, Action and Efficacy in Partial-Onset Seizures
Lacosamide: Pharmacology, Action and Efficacy in Partial-Onset Seizures
Lacosamide is an antiepileptic drug approved in the USA and Europe as adjunctive therapy for partial-onset seizures. Studies suggest that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and possibly interacts with collapsin response mediator protein-2. The efficacy of lacosamide has been shown in animal models of epilepsy and Phase II/III clinical trials. Pharmacokinetic studies show that it is renally excreted, minimally bound to plasma proteins and has no known clinically relevant drug-drug interactions. Clinical trials show that lacosamide is well tolerated; the most common adverse events were dizziness, nausea and vomiting. In a Phase II/III pooled analysis, lacosamide 200 and 400 mg/day significantly reduced partial-onset seizure frequency and improved the 50% responder rate compared with placebo.
Epilepsy, a chronic neurological condition characterized by recurrent unprovoked seizures, affects approximately 1% of the population. Seizures have traditionally been divided into those of partial onset, when the discharge starts in a restricted region of the brain, and those that are initially generalized as onset. During the last two decades, a large number of newer antiepileptic drugs (AEDs) were introduced to the market. Although some were found to be useful in the treatment of generalized seizures, all were initially evaluated and approved for the treatment of partial-onset seizures. However, despite the large number of AEDs available to the clinician, a substantial proportion of patients with epilepsy do not achieve seizure remission and many remain poorly controlled. A recent study conducted in patients with newly diagnosed epilepsy has shown that seizure freedom could be attained in less than 50% of patients following the first monotherapy trial, and that only 60-70% of patients eventually achieve seizure remission following multiple monotherapy trials. Although some patients with refractory epilepsy will benefit from epilepsy surgery, the majority of patients with epilepsy will still require chronic long-term pharmacological therapy. Many of the currently available AEDs have associated shortcomings related to idiosyncratic reactions, an undesirable pharmacokinetic profile, drug-drug interactions due to induction or inhibition of the hepatic P450 isoenzymes, slow titration schedule or frequent daily dosing. The failure of a variety of AEDs to adequately control seizures in some patients underscores the fact that there are still unmet needs for the treatment of epilepsy and available roles for additional AEDs with novel mechanisms of action and improved efficacy, safety and tolerability.
Lacosamide (LCM) is a new AED being evaluated as adjunctive therapy for partial-onset seizures in adults and for the symptomatic treatment of diabetic neuropathic pain. LCM recently received US FDA approval in the USA and EMEA marketing authorization in Europe as an add-on treatment for partial-onset seizures. In this article, we will review the pharmacology and mechanisms of action of LCM, and evaluate its efficacy and safety as adjunctive therapy at daily doses of up to 400 mg in patients with uncontrolled partial epilepsy based on a pooled analysis of three double-blind, placebo-controlled clinical trials.
Abstract and Introduction
Abstract
Lacosamide is an antiepileptic drug approved in the USA and Europe as adjunctive therapy for partial-onset seizures. Studies suggest that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and possibly interacts with collapsin response mediator protein-2. The efficacy of lacosamide has been shown in animal models of epilepsy and Phase II/III clinical trials. Pharmacokinetic studies show that it is renally excreted, minimally bound to plasma proteins and has no known clinically relevant drug-drug interactions. Clinical trials show that lacosamide is well tolerated; the most common adverse events were dizziness, nausea and vomiting. In a Phase II/III pooled analysis, lacosamide 200 and 400 mg/day significantly reduced partial-onset seizure frequency and improved the 50% responder rate compared with placebo.
Introduction
Epilepsy, a chronic neurological condition characterized by recurrent unprovoked seizures, affects approximately 1% of the population. Seizures have traditionally been divided into those of partial onset, when the discharge starts in a restricted region of the brain, and those that are initially generalized as onset. During the last two decades, a large number of newer antiepileptic drugs (AEDs) were introduced to the market. Although some were found to be useful in the treatment of generalized seizures, all were initially evaluated and approved for the treatment of partial-onset seizures. However, despite the large number of AEDs available to the clinician, a substantial proportion of patients with epilepsy do not achieve seizure remission and many remain poorly controlled. A recent study conducted in patients with newly diagnosed epilepsy has shown that seizure freedom could be attained in less than 50% of patients following the first monotherapy trial, and that only 60-70% of patients eventually achieve seizure remission following multiple monotherapy trials. Although some patients with refractory epilepsy will benefit from epilepsy surgery, the majority of patients with epilepsy will still require chronic long-term pharmacological therapy. Many of the currently available AEDs have associated shortcomings related to idiosyncratic reactions, an undesirable pharmacokinetic profile, drug-drug interactions due to induction or inhibition of the hepatic P450 isoenzymes, slow titration schedule or frequent daily dosing. The failure of a variety of AEDs to adequately control seizures in some patients underscores the fact that there are still unmet needs for the treatment of epilepsy and available roles for additional AEDs with novel mechanisms of action and improved efficacy, safety and tolerability.
Lacosamide (LCM) is a new AED being evaluated as adjunctive therapy for partial-onset seizures in adults and for the symptomatic treatment of diabetic neuropathic pain. LCM recently received US FDA approval in the USA and EMEA marketing authorization in Europe as an add-on treatment for partial-onset seizures. In this article, we will review the pharmacology and mechanisms of action of LCM, and evaluate its efficacy and safety as adjunctive therapy at daily doses of up to 400 mg in patients with uncontrolled partial epilepsy based on a pooled analysis of three double-blind, placebo-controlled clinical trials.