Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings

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The ultimate goal of epilepsy therapy remains complete freedom from seizures with minimal adverse events (AEs). Despite the introduction of numerous new antiepileptic drugs (AEDs) over the past two decades, epileptic seizures remain refractory in approximately one‐third of patients,1 highlighting the need for effective novel therapies.
Monotherapy is the gold standard for newly diagnosed epilepsy, with a second choice of monotherapy if the first treatment is not successful.3 The therapeutic choice may depend on the epileptic syndrome (etiology), seizure type (focal or generalized), and patient factors (sex, age, and comorbidity) as well as the characteristics of a drug (efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics).3 Ultimately, polytherapy may be needed to control seizures in drug‐resistant epilepsy, and thus, the potential for both pharmacodynamic synergistic effects and pharmacokinetic drug interactions must be considered.3
The intention of “rational polytherapy” is to improve efficacy by combining AEDs with different mechanisms of action (MoAs) that act on multiple drug targets, and reduce AEs by avoiding AED combinations with similar MoAs that can induce or exacerbate AEs, particularly older drugs with less favorable pharmacokinetic profiles.3 In the laboratory, the combination of zonisamide, which modulates voltage‐sensitive sodium channels and T‐type calcium currents, and perampanel, a non‐competitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, has resulted in a marked synergistic anticonvulsant effect in a rat amygdala kindling model of chronic epilepsy, suggesting the potential for increased efficacy.8 Exploration of the interactions between perampanel and other commonly administered AEDs was done in a drug‐resistant amygdala kindling model.9 When administered alone, low‐dose perampanel, levetiracetam, lamotrigine, carbamazepine, and valproic acid did not demonstrate efficacy. However, when similar low‐dose perampanel was combined with each of the individual AEDs, there were significant reductions in all seizure parameters tested. Thus, the synergic effect on seizure control to the other AEDs of perampanel add‐on might be the result of pharmacodynamic synergism between the different MoAs, although the plasma concentration of perampanel was reduced pharmacokinetically by concomitant carbamazepine (18.2%) or valproic acid (31.4%) one enzyme‐inducing AED and one enzyme‐inhibiting AED. In contrast, the plasma concentration of perampanel was increased with concomitant levetiracetam (17.2%) or lamotrigine (8.2%), suggesting a complicated and unresolved pharmacodynamic and pharmacokinetic relationship between the different drug levels of perampanel and combination with either levetiracetam or lamotrigine.9
In clinical practice, when administered by MoA (sodium channel blocker, gamma‐aminobutyric acid analog, synaptic vesicle protein 2A binding, and multiple mechanisms), AED combinations with different MoAs resulted in significantly better outcomes for treatment effectiveness (longer mean and median persistence) and healthcare resource use (lower risk for inpatient admissions and emergency department visits) than those with the same MoAs.5 It is likely that clinicians prescribe AED combinations with different MoAs in clinical practice, whether consciously or not.
In a study to ascertain the efficacy of substitution or add‐on therapy in patients for whom monotherapy was unsuccessful, a second drug was substituted for patients with intolerable AEs or added for patients who experienced lack of efficacy with the first drug.10 Overall, seizure freedom and incidence of intolerable AEs were similar for both groups, but significantly more patients prescribed a sodium channel blocker with a drug with multiple mechanisms of action became seizure‐free than those treated with other combinations (36% vs 7%; P = .05), suggesting a role for rational polytherapy.
Perampanel has been studied in the presence or absence of enzyme‐inducing AEDs (EIAEDs), sodium channel blockers, and non‐sodium channel blockers among 1480 patients receiving 2 or more concomitant AEDs at baseline. Despite the known interaction between perampanel and EIAEDs (reduction in perampanel plasma concentration), addition of perampanel improved efficacy outcomes regardless of the type of concomitant AEDs.
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