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• W2918398429 abstract "Objective: To simulate changes in steady-state plasma concentrations of perampanel following discontinuation of concomitant carbamazepine; to investigate perampanel dose alterations to maintain pre-discontinuation steady-state concentrations. Background: Perampanel plasma concentrations decline 2–3-fold following co-administration of EIAEDs, such as carbamazepine. Concentrations are expected to increase upon discontinuation of EIAEDs, although the time course to achieve a new steady state has not been established. Design/Methods: A physiologically based pharmacokinetic (PBPK) model for perampanel was developed in Simcyp® version 15.1. Predicted perampanel plasma concentrations from single- and multiple-dose simulations (1–8 mg), and from co-administration simulations with daily carbamazepine 300 mg BID, were compared with actual data from four Phase I studies in healthy adults. Two carbamazepine co-administration discontinuation scenarios were simulated: an abrupt discontinuation and a weekly 75 mg down-titration. Down-titration of perampanel (from 8 to 4 mg QD) following abrupt carbamazepine discontinuation was simulated to investigate dose alterations required to maintain pre-discontinuation steady-state concentrations. Results: The PBPK model accurately reproduced perampanel plasma concentration-time profiles from clinical studies in simulations of single- and multiple-dose regimens and with carbamazepine co-administration, supporting its use for simulations following carbamazepine discontinuation. Following simulated abrupt carbamazepine discontinuation, the return of perampanel concentrations to pre-induced levels took >20 days. Following simulated carbamazepine down-titration, the rise in perampanel concentrations took approximately 60 days. By down-titrating perampanel at the time of abrupt carbamazepine discontinuation, steady-state perampanel concentrations were found to remain similar during and after the discontinuation. Conclusions: Steady-state PBPK simulations of perampanel with the EIAED carbamazepine reproduced decreases in perampanel plasma concentrations from formal drug-drug interactions studies. Perampanel concentrations increase slowly following abrupt discontinuation of carbamazepine dosing; the rate of increase is slower following down-titration of carbamazepine versus abrupt discontinuation. Maintenance of perampanel concentrations after carbamazepine discontinuation may be achieved with down-titration of perampanel dose. Study Supported by: Eisai Inc. Disclosure: Dr. Schuck has received personal compensation for activities with Eisai Inc. as an employee. Dr. Ferry has received personal compensation for activities with Eisai Inc. as an employee. Dr. Rege has received personal compensation for activities with Eisai as an employee. Dr. Gidal has received personal compensation for activities with UCB, Eisai, and Sunovion for speaking engagements. Dr. Gidal has received personal compensation from UCB, Eisai, Sunovion, Upsher-Smith, Lundbeck LLC, and SK-Bioscience as a consultant. Dr. Hussein has received personal compensation for activities with Eisai Ltd as an employee." @default.
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• W2918398429 date "2017-04-18" @default.
• W2918398429 modified "2023-09-24" @default.
• W2918398429 title "Simulation of changes in steady-state plasma concentrations of perampanel following discontinuation of the enzyme-inducing antiepileptic drug (EIAED) carbamazepine (P3.235)" @default.
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