Therapeutic Drug Monitoring for Perampanel in Japanese Epilepsy Patients: Influence of Concomitant Antiepileptic Drugs

Background: Perampanel is a new antiepileptic drug (AED) that acts as a noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist and is mainly metabolized by cytochrome P450 (CYP) 3A4. This study evaluated the influence of concomitant AEDs on the serum concentration profile of perampanel. Methods: A total of 215 serum samples obtained from 76 patients aged 12 years or older were analyzed for routine therapeutic drug monitoring, and the concentration-to-dose ratio (CD ratio) of perampanel was compared among patients on various AED regimens. Results: In patients not taking concomitant enzyme-inducing AEDs, the mean CD ratio was 3963 ng.mL(-1) mg(-1) kg(-1) (range: 1793-13,299). By contrast, the mean CD ratio was lower in patients using enzyme-inducing AEDs [1760 (range: 892-3090), 2256 (range: 700-4703), and 1120 (range: 473 1853) ngmL(-1) mg(-1) kg(-1) in patients taking phenytoin, phenobarbital, and carbamazepine, respectively], and carbamazepine had a significantly greater reduction in the CD ratio compared with phenytoin or phenobarbital (P, 0.001). Twenty-one patients responded with >= 50% reduction of seizure frequency from baseline, and their mean serum perampanel concentration was 450 ng/mL (range: 85-1500). Conclusions: There is a large interindividual variation in CD ratio of perampanel because its metabolism is highly susceptible to interactions with enzyme-inducing AEDs. Therapeutic drug monitoring could be clinically useful for determining the influence of AED CYP3A4 inducers on perampanel concentrations.