Philip N Patsalos1, Marilia Gougoulaki, Josemir W Sander. 1. NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical & Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London and Epilepsy Society, Chalfont Centre for Epilepsy, Chalfont St Peter, United Kingdom.
Abstract
BACKGROUND: Perampanel (PMP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is a novel anti-epileptic drug (AED) licensed for the adjunctive treatment of focal and generalized epilepsy. There is limited information on PMP's pharmacokinetics and drug interaction characteristics with concomitant AEDs. We have investigated the effects of PMP dose, age, sex, and coprescribed AEDs on serum PMP concentrations. METHODS: We used the database of a therapeutic drug monitoring unit at a tertiary epilepsy referral center to identify patients who had PMP as part of their treatment and extracted clinical information from their medical notes. Sera PMP concentrations were determined using liquid chromatography/mass spectroscopy. RESULTS: In total, 160 sera from 107 patients (66 females) aged 18-70 years and weighing 40-125 kg were identified. They were prescribed a median PMP dose of 6 mg/d (range 2-12 mg/d) and were coprescribed a variety of AEDs, including enzyme-inducing [carbamazepine (CBZ) and oxcarbazepine (OXC)] and enzyme-inhibiting (valproic acid) AEDs. A linear relationship was observed between PMP dose and serum concentrations (r = 0.714, P < 0.0005). Sex and age were found not to influence PMP serum concentration. Enzyme-inducing AEDs dose-dependently decreased PMP concentrations, with CBZ and OXC decreasing mean values by 69% and 37%, respectively. In contrast, although topiramate and phenytoin also decreased mean PMP concentrations by 18% and 13%, respectively, these changes did not achieve statistical significance. CONCLUSIONS: PMP exhibits a linear dose-concentration relationship, with serum PMP concentrations being age and sex independent. CBZ and OXC can significantly decrease PMP concentrations, probably through an induction of CYP3A4-mediated metabolism.
BACKGROUND:Perampanel (PMP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is a novel anti-epileptic drug (AED) licensed for the adjunctive treatment of focal and generalized epilepsy. There is limited information on PMP's pharmacokinetics and drug interaction characteristics with concomitant AEDs. We have investigated the effects of PMP dose, age, sex, and coprescribed AEDs on serum PMP concentrations. METHODS: We used the database of a therapeutic drug monitoring unit at a tertiary epilepsy referral center to identify patients who had PMP as part of their treatment and extracted clinical information from their medical notes. Sera PMP concentrations were determined using liquid chromatography/mass spectroscopy. RESULTS: In total, 160 sera from 107 patients (66 females) aged 18-70 years and weighing 40-125 kg were identified. They were prescribed a median PMP dose of 6 mg/d (range 2-12 mg/d) and were coprescribed a variety of AEDs, including enzyme-inducing [carbamazepine (CBZ) and oxcarbazepine (OXC)] and enzyme-inhibiting (valproic acid) AEDs. A linear relationship was observed between PMP dose and serum concentrations (r = 0.714, P < 0.0005). Sex and age were found not to influence PMP serum concentration. Enzyme-inducing AEDs dose-dependently decreased PMP concentrations, with CBZ and OXC decreasing mean values by 69% and 37%, respectively. In contrast, although topiramate and phenytoin also decreased mean PMP concentrations by 18% and 13%, respectively, these changes did not achieve statistical significance. CONCLUSIONS:PMP exhibits a linear dose-concentration relationship, with serum PMP concentrations being age and sex independent. CBZ and OXC can significantly decrease PMP concentrations, probably through an induction of CYP3A4-mediated metabolism.