Abstracts

Rationale: Perampanel (PER) is a selective, noncompetitive AMPA-antagonist that has been approved as adjunctive treatment for partial-onset seizures. In vitro studies and phase I trials indicate that PER is metabolized almost exclusively by CYP3A4, with an elimination half-life (t1/2) of approximately 105 hours. Pharmacokinetic (PK) interactions enzyme inhibition or induction will be important to anticipate and manage in epilepsy patients. Here we report results from a phase I drug-drug interaction (DDI) study with the potent CYP3A4 inhibitor ketoconazole on PER PK (Study 005), as well as supplementary in silico predictions further exploring this interaction.Methods: A phase I, randomized, open-label, 2-period, 2-treatment, 2-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 1mg PER dose while fasted (Day 1); in the other period, subjects received ketoconazole 400mg once daily for 10 days with a single 1mg PER dose while fasted (Day 3). Blood samples were drawn at multiple timepoints up to 288hr after the PER dose. PK parameters of PER were calculated by noncompartmental analysis and safety was recorded. An integrated physiologically based PK model built in Simcyp provided additional insight into this interaction. DDI intensity was measured by the ratio of systemic exposure (area under plasma concentration-time curve [AUC]) of PER in the presence and absence of concomitant ketoconazole.Results: Single oral doses of 1mg PER and once-daily oral doses of ketoconazole 400mg were safe and well tolerated. Maximum plasma concentration (Cmax) of PER and time to Cmax (tmax) showed no apparent differences when PER was administered alone or with ketoconazole (Table 1). However, coadministration of ketoconazole with PER resulted in increased PER AUC of 20% (p<0.001). This increase, although statistically significant, was a <2.0-fold AUC change and alone would not suggest a significant DDI. To further explore these findings, DDI simulations using trial conditions of Study 005 also predicted an AUC ratio increase <2-fold. Simulations further suggested that in order to observe an interaction of greater magnitude (AUC fold-increase >2.0), larger/more frequent doses (eg, 200mg every 6hr) of ketoconazole given for a greater time period (eg, 30 days) would be necessary. Additionally, simulations suggested that a significant interaction with coadministration of PER and an inhibitor more potent than ketoconazole could not be ruled out.Conclusions: For drugs such as PER, with very long t1/2, study design is critical when interpreting PK data. Although a negligible effect on PER PK was observed following coadministration of ketoconazole 400mg/day for 10 days, this is likely due in part to the relatively brief dosing period of ketoconazole and PER (<3 t1/2 of PER). Short-term administration of a potent CYP3A4 inhibitor may not result in significant increases in PER exposure, but a significant increase developing over time following chronic dosing cannot be ruled out.