Abstracts

Rationale: Perampanel (PER) is a selective AMPA receptor antagonist currently being evaluated as adjunctive therapy in patients with refractory partial seizures. PER is metabolized primarily via CYP3A4, yet has a relatively long elimination half-life (T1/2) of 105 h, and as such, is given on a once-daily (QD) basis. Enzyme-inducing antiepileptic drugs (EIAEDs) may substantially reduce PER T1/2 due to an increase in oral clearance (CL/F). Carbamazepine (CBZ) increases PER CL/F ~3-fold, while oxcarbazepine (OXC) or phenytoin (PHT) increases CL/F ~2-fold. AEDs with a long T1/2 may facilitate medication adherence by reducing administration frequency and may minimize peak to trough fluctuations, especially in the setting of erratic adherence. In addition, the impact of a delayed or missed dose of PER on plasma concentrations may be less with PER than with short T1/2 AEDs. Hence, we sought to examine the pharmacokinetics (PK) of PER following simulated missed/delayed dose paradigms. Methods: Simulations were done using validated PER PK parameters, derived from 19 Phase I studies in 606 subjects, to study the effect on PER concentration of (1) missing a dose followed by delayed replacement of the missed dose; (2) missing a dose followed by resumption of scheduled therapy; (3) missing a dose in the presence/absence of CBZ. Simulations were done for a typical patient receiving 8 mg PER once daily, using NONMEM v7.2 in conjunction with PDx-pop v5. Results: Simulation results are presented in Table 1. Following QD dosing, peak-trough fluctuation for PER is relatively flat, as would be expected from its long T1/2. Fluctuation index (FI) is greater when PER is given in the presence of EIAEDs due to the shorter T1/2. Following a missed dose and in the absence of EIAEDs, PER trough concentrations (C_min) would be expected to decline mildly; while in the presence of EIAEDs, the predicted reduction in C_min is moderate. Replacing a missed dose, even after a 6- or 12-h time period, results in a mild decline in C_min in the induced and noninduced state. Changes in peak (C_max) were also only minor following dose replacement. Conclusions: While perfect medication adherence is always preferable, it is often not consistently achieved. Our results corroborate that given the PK characteristics of PER, plasma concentration fluctuation is less than might be expected in the case of a short half-life drug, and supports QD dosing. PER FI increases with EIAEDs. In that the efficacy of PER appears to be related to drug exposure (ie, plasma concentration), these data suggest that declines in trough concentrations are likely to be modest in the event of a missed dose, and that supplementing a missed dose 6-12 h later can lessen these predicted declines without resulting in excessive "spikes" in PER plasma concentrations.