Changes in perampanel levels during de‐induction: Simulations following carbamazepine discontinuation

OBJECTIVE: To evaluate the time course of changes in perampanel levels when co‐administered with carbamazepine, and following carbamazepine discontinuation, using a physiologically based pharmacokinetic (PBPK) model. METHODS: The PBPK model was developed, verified using clinical PK data, and used to simulate the effect of abrupt discontinuation and down‐titration (75 mg twice daily [bid]/wk) of co‐administered carbamazepine 300 mg bid on the PK of perampanel once daily (qd). Perampanel dose tapering (8‐4 mg) and up‐titration (2‐6 mg) were simulated during abrupt carbamazepine 300 mg bid discontinuation to identify a titration schedule that minimizes changes in perampanel plasma concentrations. RESULTS: The PBPK model accurately reproduced perampanel plasma concentration‐time profiles from clinical studies in single‐ and multiple‐dose regimen simulations, including multiple‐dose carbamazepine co‐administration. The time course of return to pre‐induced perampanel levels occurred more slowly following carbamazepine down‐titration (~48 days after first down‐titration) vs abrupt discontinuation (~25 days). Perampanel dose tapering (8‐4 mg) at abrupt carbamazepine discontinuation produced minimal changes in steady‐state concentrations, which returned to the levels observed during carbamazepine co‐administration in ~15 days from the time of carbamazepine discontinuation. When perampanel was up‐titrated in the presence of carbamazepine, return to steady state occurred more slowly when carbamazepine was down‐titrated weekly (~45 days) vs abrupt discontinuation (~24 days). CONCLUSION: This PBPK model simulated and predicted optimal perampanel dose tapering and up‐titration schedules for maintaining perampanel levels during conversion to monotherapy. These results may guide physicians when managing conversion from perampanel polytherapy with concomitant enzyme‐inducing anti‐seizure medications to monotherapy.