Abstracts

Rationale: Perampanel is a once-daily oral anti-seizure drug for partial-onset seizures (POS) and primary generalized tonic-clonic seizures (PGTCS). Here, we report population pharmacokinetic/pharmacodynamic (PK/PD) analyses to explore perampanel exposure–response relationships for cognition and safety in pediatric patients (aged 4 to <12 years) with POS or PGTCS. Methods: Data from POS and PGTCS subjects were pooled from an open-label, Phase III study of adjunctive perampanel oral suspension (0.5 mg/mL; NCT02849626). Graphical PK/PD analyses were used to assess potential relationships between: (1) model-predicted average perampanel concentration at steady state (Cav,ss) and cognitive endpoints (change from baseline in A-B Neuropsychological Assessment [ABNAS], Child Behavior Checklist [CBCL], and Lafayette Grooved Pegboard Test [LGPT]); (2) perampanel Cav,ss and the most frequent (occurring in ≥10 subjects) treatment-emergent adverse events (TEAEs); and (3) model-predicted maximum perampanel concentration at steady state (Cmax,ss) and the most frequent TEAEs. If a relationship was apparent, PK/PD modeling using binary logistic regression was performed. Results: Overall, the analyses for cognition and safety included 156 subjects who received perampanel (POS, n=129; PGTCS, n=27). Graphical PK/PD analysis for cognition found no discernible relationship between perampanel Cav,ss and change from baseline for ABNAS (n=148), CBCL (aged ≤5 years, n=19; aged >5 years, n=115), or LGPT (dominant hand, n=117; non-dominant hand, n=113), thus no further PK/PD modeling was performed. TEAEs that occurred in ≥10 subjects included nasopharyngitis (n=23 [14.7%]), somnolence (n=21 [13.5%]), aggression/agitation/irritability (n=20 [12.8%]), pyrexia (n=14 [9.0%]), and influenza (n=10 [6.4%]). No relationship between perampanel Cav,ss and the occurrence of the most common TEAEs was observed. Graphical assessment showed possible relationships between model-predicted perampanel Cmax,ss and the occurrence of somnolence, aggression/agitation/irritability, and pyrexia (Figure 1). However, PK/PD modeling found no statistically significant effect of perampanel exposure on the occurrence of these TEAEs. Conclusions: These assessments suggest there is no exposure–response relationship between perampanel and cognitive or safety outcomes in pediatric patients (aged 4 to <12 years) with POS or PGTCS, supporting the conclusion that cognitive function is not clinically impaired by perampanel administration. Funding: Eisai Inc.