Effect of enzyme inhibition on perampanel pharmacokinetics: Why study design matters

OBJECTIVES Perampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12years and older. In vitro studies and Phase I trials indicate that perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t1/2) averaging approximately 105h. Understanding of pharmacokinetic (PK) interactions-enzyme inhibition or induction-and anticipating their occurrence are important for management of patients with epilepsy. Here we report PK results from a Phase I drug-drug interaction (DDI) study (Study 005) combining perampanel with the CYP3A inhibitor ketoconazole, as well as supplementary in silico predictions further exploring this interaction. METHODS A Phase I, randomized, open-label, two-period, two-treatment, two-way crossover study was conducted in 26 healthy adult male volunteers. Subjects were randomized to 1 of 2 treatment sequences. In one period, subjects received a single 1-mg fasting dose of perampanel (Day1); in the other period, subjects received ketoconazole 400mg once daily for 10days with a single 1-mg perampanel dose while fasting (Day3). Blood samples were drawn at multiple time points up to 288h after the perampanel dose. Pharmacokinetic parameters of perampanel were calculated by noncompartmental analysis, and safety was recorded. An integrated, physiologically based PK model built in Simcyp® provided additional insight into this interaction. Drug-drug interaction intensity was measured by the ratio of systemic exposure (area under plasma concentration-time curve [AUC]) of perampanel in the presence or absence of concomitant ketoconazole. RESULTS Single oral doses of 1mg perampanel and once-daily oral doses of ketoconazole 400mg were safe and well tolerated. Maximum perampanel plasma concentration (Cmax) and time to Cmax showed no apparent differences when perampanel was administered alone versus with ketoconazole. Ketoconazole co-administration resulted in an approximate 20% increase in perampanel AUC (P<0.001). This increase, although statistically significant, was a<2.0-fold AUC change and alone would suggest a modest effect of ketoconazole. To further explore these results, DDI simulations were performed to query the findings and test additional study conditions. Using the actual trial conditions of Study 005, the simulations also predicted an AUC ratio increase <2-fold, providing verification of the simulation assumptions and the modest effect of ketoconazole for 10days. Simulations further suggested that an interaction effect of ketoconazole on perampanel exposure (>2-fold) of potential clinical significance could be predicted when using larger doses of ketoconazole (e.g., 200mg every 6h) coadministered for a greater time period (e.g., 30days), with AUC ratio as high as 3.36. Additionally, simulations suggested that a significant interaction with co-administration of perampanel and an inhibitor more potent than ketoconazole (such as itraconazole) could not be ruled out. CONCLUSIONS Selecting an appropriate study design is critical to fully characterize the PK interaction for drugs such as perampanel that have a long t1/2. Although a negligible effect on perampanel PK was observed following co-administration of ketoconazole 400mg/day for 10days, this is likely due in part to the relatively brief co-administration period of ketoconazole and perampanel (<3 times the t1/2 of perampanel). While short-term administration of a CYP3A inhibitor may not significantly increase perampanel exposure, such increases may be expected following chronic and larger dosing or with a more potent inhibitor.