Abstracts

Rationale: In the US, Japan, and Korea, perampanel is approved for FOS, with/without focal to bilateral tonic-clonic seizures, in patients aged ≥ 4 years (monotherapy/adjunctive), and generalized tonic-clonic seizures in patients aged ≥ 12 (≥ 7, Korea) years (adjunctive). A previous post hoc analysis of perampanel 4-mg/day monotherapy from FREEDOM (Study 342; NCT03201900) showed that there was no clear association between perampanel plasma levels and seizure control or occurrence of treatment-emergent adverse events (TEAEs). We expand on previous findings by focusing on patients who titrated up to 8-mg/day monotherapy during the FREEDOM Core Study to further explore the relationship between perampanel plasma concentrations and clinical efficacy/tolerability.

Methods: During the Core Study, patients received perampanel 4 mg/day (4-week Pretreatment; 32-week Treatment [6-week Titration; 26-week Maintenance]). If a patient had a seizure, they could be up-titrated to 8 mg/day (4-week Titration; 26-week Maintenance). For patients who entered the 8-mg/day Treatment Phase, blood samples for pharmacokinetic (PK) assessment were collected at the end of the 8-mg/day Titration Period (Week 4) and during the 8-mg/day Maintenance Period. Perampanel plasma concentrations at Week 4 are summarized in the modified Intent-to-Treat (mITT) Analysis Set (defined as patients who entered the 4-mg/day Maintenance Period with ≥ 1 post-dose efficacy assessment [for these analyses, only patients who then entered the 8-mg/day Treatment Phase are included]), stratified by seizure-free status and with/without TEAEs during the 8-mg/day Maintenance Period.

Results: Overall, 89 patients received ≥ 1 perampanel dose; 73 patients entered the 4-mg/day Maintenance Period (mITT Analysis Set); 21 patients entered the 8-mg/day Treatment Phase. During the 8-mg/day Treatment Phase, PK data were available for 12 patients. At Week 4 (end of 8-mg/day titration), there was large intersubject variability in perampanel plasma concentrations with no clear association between perampanel levels and seizure-free status (Table 1; P=0.1161 [2-tailed t-test]). During the 8-mg/day Maintenance Period, 10/12 patients with PK data experienced a TEAE; 3 patients had treatment-related TEAEs. In general, there was wide intersubject variability in perampanel plasma concentrations in patients with and without TEAEs at Week 4 (Figure 1). There was overlap between perampanel levels in patients with/without treatment-related TEAEs and with/without a TEAE of dizziness. However, the small number of patients with available PK data and experiencing TEAEs should be noted.

Conclusions: Although no clear association between perampanel plasma levels and treatment outcome was observed with perampanel 8-mg/day monotherapy, the sample size is too small to draw conclusions. A previous analysis from FREEDOM in patients receiving perampanel 4-mg/day monotherapy suggested that perampanel dosing should be individualized, based on observed clinical efficacy/tolerability.

Funding: Please list any funding that was received in support of this abstract.: Eisai Co., Ltd.