Abstracts

Rationale: Perampanel (PER), a selective, noncompetitive AMPA receptor antagonist, has been evaluated as adjunctive treatment for partial-onset seizures (POS) in patients older than 12 years of age. Following oral administration, PER is rapidly and completely absorbed. PER is mainly eliminated by oxidative metabolism, primarily mediated by the CYP3A4 isozyme. PER absorption and elimination pharmacokinetics (PKs) are linear, regardless of concomitant antiepileptic drugs (AEDs). Population PK analyses has shown that 3 known CYP3A4-inducing AEDs (EIAEDs) increased PER oral clearance (CL/F). Coadministration of carbamazepine (CBZ) increased CL/F ~3-fold, while oxcarbazepine (OXC) or phenytoin (PHT) increased CL/F ~2-fold. Given that PER efficacy appears to be related to systemic exposure (as assessed here by average steady-state concentration), it is clinically relevant to evaluate the impact of concomitant EIAEDs on both efficacy and safety. Methods: Patients with refractory POS enrolled in the 3 phase 3 trials were aged ≥12 years and were receiving 1 to 3 concomitant AEDs. Following a 6-week baseline, patients were randomized to once-daily double-blind treatment (6-week titration, 13-week maintenance) with placebo, PER 8 mg or 12 mg (studies 304 or 305); and placebo, PER 2 mg, 4 mg, or 8 mg (study 306). Study endpoints included change in seizure frequency/28 days, 50% responder rate, and safety. Results: Population PK analyses indicate that PER plasma concentrations increase proportionally with doses between 2-12 mg. As expected, in the presence of EIAEDs, PER average steady-state plasma concentrations (C_avss) are reduced but also increase linearly in a dose-dependent manner (Table 1). Median % change in seizure frequency as well as responder rates was more robust when PER was given concomitantly with non-EIAEDs, but reduced in the presence of EIAEDs (Table 2). With regard to safety, the overall incidence of treatment-emergent adverse events was similar regardless of the presence of EIAEDs. The probability of occurrence of some AEs such as fatigue, somnolence, gait disturbances, dizziness, weight increase, irritability, dysarthria, and euphoric mood increased with an increase in PER plasma concentration. Conclusions: Perampanel demonstrates efficacy in the presence of, as well as absence of EIAEDs. In particular, efficacy appears to be related to systemic exposure, with increased efficacy rates being observed with higher average steady-state plasma concentrations. As expected, concomitant administration of PHT, CBZ or OXC reduces plasma PER concentrations. Taken together, these observations support the important concept of dosing to clinical effect. Clinicians should recognize that they may need to use higher doses of perampanel when patients are also receiving inducing drugs. Clearly, recognition of these pharmacokinetic interactions will be important in the optimization of this novel medication.