Abstracts

Rationale:
In the US, perampanel is approved for partial-onset seizures (adjunctive and monotherapy) in patients aged ≥ 4 years, and adjunctive treatment of primary generalized tonic-clonic seizures in patients aged ≥ 12 years. Perampanel is available as oral tablet and suspension formulations and is currently being developed as an intravenous (IV) infusion that has demonstrated bioequivalence relative to oral dosing for exposure, whilst single-dose maximum observed plasma concentration (Cmax) was 1.06-, 1.35- and 1.61-fold higher following 90-, 60- and 30-min IV infusions, respectively. The aim of this pharmacokinetic (PK) modeling and simulation analysis was to assess the interchangeability between oral and IV administrations.
Method:
Analyses were based on 2754 pooled PK observations from 97 healthy adults enrolled in two open-label, single-dose, crossover studies. Participants received a single 12-mg dose of perampanel IV infusion and a single 12-mg oral tablet (Study 050; NCT03376997) or a single 12-mg oral tablet (Study 048; NCT02279485). A 3-compartment model was fitted to the PK data and used to simulate plasma concentration–time profiles using NONMEM® Version 7.3. Two scenarios were assessed: (1) switching from perampanel 12-mg oral to 12-mg IV and back to oral in patients receiving perampanel maintenance therapy and (2) treatment initiation of perampanel (2-mg oral vs 2-mg IV) in perampanel-naïve patients. Each scenario simulated 20 trials with 50 participants (total n=1000 per scenario and infusion duration of 90, 60 or 30 mins). Exposure parameters assessed included Cmax, Cmax at steady-state (Css,max) and trough plasma concentration at steady-state (Css,min). Safety, including adverse events (AEs), was monitored in both trials.
Results:
Under the treatment maintenance scenario, simulated perampanel plasma concentration–time profiles indicated Css,max bioequivalence when oral perampanel is switched to 90- or 60-min IV infusions and for the majority of simulations following 30-min infusions (Figure 1). For patients initiating perampanel treatment, the predicted mean Cmax following 90-, 60- and 30-min infusions was 1.25-, 1.34-, and 1.69-fold higher vs oral dosing  (Figure 2). Overall, 34/48 (70.8%) participants in Study 050 experienced a treatment-related AE, all of which were mild (n=34) or moderate (n=2). AEs occurred on the day of treatment in 51.1 % of patients (n=24/47) after oral tablets vs 42.9% (n=3/7), 57.9% (n=11/19) and 52.6% (n=10/19) with 90-, 60- and 30-min IV infusions. No deaths occurred and no new safety concerns were identified.
Conclusion:
Modeling and simulation analyses support the interchangeability of perampanel IV 90-, 60- and 30-min infusions and oral dosing for temporary use in patients receiving stable doses of maintenance therapy. Whilst Cmax was slightly higher after treatment initiation with 2-mg perampanel IV vs oral dosing, this difference is not considered clinically significant as 2-mg starting doses are sub-therapeutic. The safety profile of perampanel IV infusions was similar to oral tablets.
Funding:
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Funding:
: Eisai Inc.