RESUMO
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.
