Armel Stockis1, Maria L Sargentini-Maier2, Martin J Brodie3. 1. UCB Pharma, Braine l'Alleud, Belgium. Electronic address: Armel.Stockis@ucb.com. 2. UCB Pharma, Braine l'Alleud, Belgium. 3. Epilepsy Unit West Glasgow, ACH-Yorkhill, Glasgow, Scotland, UK.
Abstract
OBJECTIVE: This Phase I, open-label, dose-escalation study investigated the effects of steady-state brivaracetam on the pharmacokinetics of carbamazepine in patients with epilepsy, with and without valproate co-administration. Valproate and brivaracetam inhibit epoxide hydrolase and increase carbamazepine epoxide levels. METHODS: Adult patients with epilepsy being chronically treated with carbamazepine alone (n=9) or with carbamazepine and valproate (n=9) received brivaracetam during successive 1-week periods at doses of 50mg, 100mg, 200mg, and 100mg twice daily (bid). Doses of carbamazepine and valproate must have been stable for at least 3 months. Trough plasma concentrations of carbamazepine, carbamazepine epoxide, and diol metabolites were determined on Days 1, 8, 15, 22, and 29, and at the end of study visit (ESV, 2-3weeks later). RESULTS: Eighteen patients with median (range) age of 45 (20-62) years and body weight of 74 (59-124) kg were enrolled and completed the study. In patients treated with carbamazepine alone, brivaracetam dose-dependently increased mean trough levels of carbamazepine epoxide from 1.38μg/mL on Day 1 pre-dose to 2.16μg/mL (+57%) on Day 8 (50mg bid), 2.72μg/mL (+97%) on Day 15 (100mg bid), 3.02μg/mL (+119%) on Day 22 (200mg bid), 2.67μg/mL (+94%) on Day 29 (100mg bid), and 1.22μg/mL (-12%) at ESV, respectively. In patients on carbamazepine and valproate, carbamazepine epoxide increased from 1.98μg/mL at baseline to 2.72μg/mL (+37%), 3.70μg/mL (+87%), 4.43μg/mL (+124%), 3.11μg/mL (+57%), and 1.94μg/mL (-2%), respectively. There was no trend for change in carbamazepine, carbamazepine diol or valproate levels. Brivaracetam levels increased linearly with dose. Brivaracetam was well tolerated. CONCLUSIONS: Carbamazepine epoxide plasma concentrations were approximately doubled by brivaracetam 100 or 200mg bid. Data are consistent with a dose-dependent and reversible inhibition of epoxide hydrolase by brivaracetam. Carbamazepine epoxide was approximately 0.7μg/mL higher in presence of valproate. There is no need to limit brivaracetam dosing when used concomitantly with carbamazepine. Copyright Â
OBJECTIVE: This Phase I, open-label, dose-escalation study investigated the effects of steady-state brivaracetam on the pharmacokinetics of carbamazepine in patients with epilepsy, with and without valproate co-administration. Valproate and brivaracetam inhibit epoxide hydrolase and increase carbamazepine epoxide levels. METHODS: Adult patients with epilepsy being chronically treated with carbamazepine alone (n=9) or with carbamazepine and valproate (n=9) received brivaracetam during successive 1-week periods at doses of 50mg, 100mg, 200mg, and 100mg twice daily (bid). Doses of carbamazepine and valproate must have been stable for at least 3 months. Trough plasma concentrations of carbamazepine, carbamazepine epoxide, and diol metabolites were determined on Days 1, 8, 15, 22, and 29, and at the end of study visit (ESV, 2-3weeks later). RESULTS: Eighteen patients with median (range) age of 45 (20-62) years and body weight of 74 (59-124) kg were enrolled and completed the study. In patients treated with carbamazepine alone, brivaracetam dose-dependently increased mean trough levels of carbamazepine epoxide from 1.38μg/mL on Day 1 pre-dose to 2.16μg/mL (+57%) on Day 8 (50mg bid), 2.72μg/mL (+97%) on Day 15 (100mg bid), 3.02μg/mL (+119%) on Day 22 (200mg bid), 2.67μg/mL (+94%) on Day 29 (100mg bid), and 1.22μg/mL (-12%) at ESV, respectively. In patients on carbamazepine and valproate, carbamazepine epoxide increased from 1.98μg/mL at baseline to 2.72μg/mL (+37%), 3.70μg/mL (+87%), 4.43μg/mL (+124%), 3.11μg/mL (+57%), and 1.94μg/mL (-2%), respectively. There was no trend for change in carbamazepine, carbamazepine diol or valproate levels. Brivaracetam levels increased linearly with dose. Brivaracetam was well tolerated. CONCLUSIONS:Carbamazepine epoxide plasma concentrations were approximately doubled by brivaracetam 100 or 200mg bid. Data are consistent with a dose-dependent and reversible inhibition of epoxide hydrolase by brivaracetam. Carbamazepine epoxide was approximately 0.7μg/mL higher in presence of valproate. There is no need to limit brivaracetam dosing when used concomitantly with carbamazepine. Copyright Â