Pharmacotherapy of epilepsy: newly approved and developmental agents

Abstract

This article discusses seven newly available antiepileptic drugs (AEDs) and agents in phase III development. Lacosamide, licensed as an adjunctive treatment for partial-onset seizures, primarily acts by enhancing sodium channel slow inactivation. At daily doses of 200-600 mg, the drug significantly reduced partial-onset seizures in adults with refractory epilepsy. The most common adverse effects are CNS related. Rufinamide, available as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome, has an unclear mechanism of action, although it does block voltage-dependent sodium channels. Coadministration of valproic acid significantly increases rufinamide circulating concentrations. The drug has been shown to have efficacy for partial-onset, primary generalized tonic-clonic, tonic-atonic, absence and atypical absence seizures. Adverse effects are mainly somnolence, nausea and vomiting. Eslicarbazepine acetate, a carbamazepine analogue, was recently licensed as adjunctive treatment for partial-onset seizures. Eslicarbazepine acetate acts at voltage-gated sodium channels, although the precise mechanism of action is unclear. The drug had efficacy for partial-onset seizures in three randomized, double-blind, placebo-controlled studies, using 400, 800 or 1200 mg/day. Adverse effects include dizziness and somnolence. Retigabine (ezogabine) exerts its anticonvulsant effect through the opening of neuronal voltage-gated potassium channels. Following significant seizure reduction rates at dosages of 600, 900 and 1200 mg/day, license applications have been submitted for its use as adjunctive treatment for patients with partial-onset seizures. Dose-related adverse effects include somnolence, confusion and dizziness. Brivaracetam is the n-propyl analogue of levetiracetam. Mixed results have been obtained in phase III studies in patients with partial-onset seizures, and further trials in children, patients with photosensitive epilepsy and patients with partial-onset seizures are ongoing. Dizziness, headache and somnolence are the most common adverse effects reported. Perampanel was designed as an AMPA-type glutamate receptor antagonist. Following encouraging results from phase II studies in patients with refractory partial-onset seizures, recruitment for phase III trials is almost complete. Ganaxolone is a neurosteroid with potent antiepileptic activity that modulates GABA(A) receptors in the CNS. Ganaxolone has shown promise in a variety of seizure types. Dizziness and somnolence have been reported in some patients. The availability of new AEDs has widened the choices for clinicians treating patients with epilepsy. However, given the minimal improvement in prognosis and disappointing efficacy outcomes in double-blind, placebo-controlled, dose-ranging regulatory trials, it seems unlikely that these novel agents will have a major impact on outcomes for people with epilepsy.