Novel Medications for Epilepsy

Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the last 2 decades, the proportion of individuals with pharmaco-resistant epilepsy has not been reduced substantially compared with the late 1960s. All currently available AEDs also have limitations in terms of adverse effects and susceptibility to be involved in clinically important drug-drug interactions. Therefore, the search for potentially more effective and better tolerated agents is continuing. This article reviews the pharmacological and clinical profile of the latest compounds to receive marketing authorization.

Since the beginning of 2008, three novel AEDs, lacosamide, eslicarbazepine acetate and retigabine (also known as ezogabine), have become commercially available in Europe, with lacosamide and retigabine also being licensed in the US. All three agents are indicated for the adjunctive treatment of focal seizures in adults.

Eslicarbazepine acetate is a produg for eslicarbazepine, which acts by blocking voltage-dependent sodium channels. Lacosamide enhances the slow inactivation phase of voltage-dependent sodium channels, and retigabine potentiates neuronal M-currents by opening Kv 7.2–7.5 potassium channels.

All three agents, which are well absorbed from the gastrointestinal tract, exhibit linear pharmacokinetics. Lacosamide is also available as an intravenous formulation intended as replacement therapy for patients temporarily unable to take oral medications. All three drugs are eliminated partly unchanged in urine and partly by biotransformation through glucuronide conjugation (eslicarbazepine, retigabine), N-acetylation (retigabine) and oxidative demethylation (lacosamide). The half-life is in the order of 8–20 hours for eslicarbazepine, 12–16 hours for lacosamide and 6–10 hours for retigabine. Based on the limited information available to date, the ability of these agents to cause pharmacokinetic drug interactions appears to be relatively modest, although eslicarbazepine can cause a significant decrease in the blood levels of ethinylestradiol, levonorgestrel and simvastatin.

The approved effective dose ranges are 200–400 mg/day in two divided doses for lacosamide, 800–1200 mg/day once daily for eslicarbazepine acetate, and 600–1200 mg/day in three divided doses for retigabine. In phase III, randomized, double-blind, adjunctive therapy trials, responder rates (proportion of patients with ≥50% reduction in seizure frequency vs baseline) at the highest approved dose were comparable for the three drugs (eslicarbazepine acetate: 37–43% vs 13–20% for placebo; lacosamide: 38–41% vs 18–26% for placebo; retigabine: 33–44% vs 16–18% for placebo). The adverse events most commonly reported with active treatment compared with placebo included dizziness, diplopia and nausea for lacosamide; dizziness, somnolence and nausea for eslicarbazepine acetate; and dizziness, somnolence and fatigue for retigabine.

The role of these agents in the treatment algorithm will be increasingly defined as clinical experience accumulates. At present, their use is largely restricted to the adjunctive treatment of focal seizures, with or without secondary generalization, in adults with epilepsy who failed to achieve seizure freedom after having tried two or more first-line agents.