Recent Studies Elucidate the Advantages of the Newest AEDs

NAPLES, FL—The new antiepileptic drugs (AEDs) perampanel, eslicarbazepine, and brivaracetam have been the subjects of much research in recent years. Investigators have shed light on areas such as drug interactions, tolerability, and drug response in different patient populations, according to Bassel W. Abou-Khalil, MD, Professor of Neurology and Director of the Epilepsy Center at Vanderbilt University Medical Center in Nashville.

Bassel W. Abou-Khalil, MD

Perampanel

Perampanel is a noncompetitive AMPA glutamate receptor antagonist that was originally approved in 2012 as adjunctive therapy for patients with partial-onset seizures, said Dr. Abou-Khalil at the 45th Annual Meeting of the Southern Clinical Neurological Society. The drug was approved as adjunctive treatment for primary generalized tonic-clonic seizures in 2015. In 2017, the FDA extrapolated from the drug’s efficacy and safety as adjunctive therapy and granted it additional approval as monotherapy for partial-onset seizures, making it the first AED to be approved via this regulatory pathway.

Although perampanel does not appear to have significant interactions with other new AEDs, it has been shown that the 12-mg dose, but not the 8-mg dose, reduces levels of the oral contraceptive levonorgestrel by approximately 40%. Enzyme inducers such as phenytoin, carbamazepine, and phenobarbital decrease perampanel levels, Dr. Abou-Khalil said. Perampanel has a black box warning about aggression and hostility, particularly in patients taking the 12-mg dose. “Research suggests that severe psychiatric adverse effects are rare and appear to be more common in patients with intellectual disability,” Dr. Abou-Khalil said.

Two case reports have documented significant responses to adjunctive perampanel in patients with Lafora disease, a fatal autosomal-recessive genetic disorder. These patients had significantly reduced or remitted myoclonus and seizures and regained the ability to ambulate, Dr. Abou-Khalil said. Similarly, in a small study involving 10 patients with Lafora disease taking adjunctive perampanel, four had a 74% or greater reduction in seizures from baseline, and seven had major improvements in myoclonus. “In this study, there were no significant improvements in the progressive disability and cognitive decline that Lafora disease patients experience. However, it still is an exceptional drug for this very difficult type of epilepsy,” Dr. Abou-Khalil said.

In another study, perampanel also had significantly beneficial effects on myoclonus and conferred seizure freedom in 12 patients with Unverricht-Lundborg disease, a rare, inherited form of epilepsy that can interfere with walking and performance of everyday activities.

Eslicarbazepine Acetate

“Eslicarbazepine acetate, which has the same mechanism of action as oxcarbazepine, blocks sodium channels and stabilizes the inactive state of the voltage-gated sodium channel,” Dr. Abou-Khalil said. Oxcarbazepine is metabolized to both S-licarbazepine and the inactive R-licarbazepine and is detectible in serum as the parent compound, while eslicarbazepine acetate is rapidly converted primarily to S-licarbazepine and is generally undetectable in serum as the parent compound. “With eslicarbazepine, we are giving the patient more of the active metabolite of oxcarbazepine, while avoiding the adverse effects of the parent drug and the inactive element,” said Dr. Abou-Khalil.

Eslicarbazepine acetate was first approved in 2013 as add-on therapy, then in 2015 as monotherapy to treat partial-onset seizures in adults. In 2017, eslicarbazepine’s indication was expanded to include treatment of partial-onset seizures in children and adolescents age 4 and older.

Risk of common adverse effects, which include dizziness, somnolence, vomiting, blurred vision, and vertigo, are increased with concomitant use of other sodium-channel blockers, particularly carbamazepine. “However, the way the drug is titrated seems to be more important than the final dose,” Dr. Abou-Khalil said. One study demonstrated that the incidence of adverse events was lower in patients who initiated eslicarbazepine at 400 mg/day versus 800 mg/day. As much as 3% of patients taking 1,200 mg/day may develop rash.

Furthermore, research shows that elderly patients have a higher incidence of adverse effects than younger patients. “This suggests that eslicarbazepine acetate may not be an ideal drug in the older age group.”

Eslicarbazepine acetate also may have beneficial effects on lipid levels. In a retrospective cohort study of 36 adults with epilepsy taking eslicarbazepine acetate as add-on treatment, total and LDL cholesterol values were significantly decreased after at least six months of treatment, compared with the period before treatment (191.3 mg/dL vs 179.7 mg/dL, and 114.58 mg/dL vs 103.11mg/dL, respectively). HDL values were significantly increased (57.5 mg/dL vs 63.9 mg/dL before treatment).

Brivaracetam

Brivaracetam, approved in 2016 as adjunctive treatment for partial-onset seizures and in 2017 as monotherapy, binds to synaptic vesicle glycoprotein 2A with a 20-fold higher affinity than levetiracetam and higher brain permeability. “As far as drug interactions are concerned, enzyme inducers will reduce brivaracetam levels. In turn, brivaracetam may increase 10,11-carbamazepine epoxide and phenytoin concentrations,” Dr. Abou-Khalil explained.