Pharmacokinetic interaction of brivaracetam on carbamazepine in adult patients with epilepsy, with and without valproate co-administration

- Phase I open-label study in 18 adults with epilepsy taking carbamazepine ± valproate.
- Brivaracetam 100 and 200 mg bid approximately doubled plasma carbamazepine epoxide.
- Data consistent with dose-dependent inhibition of epoxide hydrolase by brivaracetam.
- Carbamazepine-epoxide concentrations ∼0.7 μg/mL higher in the presence of valproate.
- There is no need to limit brivaracetam dosing when used concomitantly with carbamazepine.

ObjectiveThis 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.MethodsAdult 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 50 mg, 100 mg, 200 mg, and 100 mg 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, 2-3 weeks later).ResultsEighteen 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 1.38 μg/mL on Day 1 pre-dose to 2.16 μg/mL (+57%) on Day 8 (50 mg bid), 2.72 μg/mL (+97%) on Day 15 (100 mg bid), 3.02 μg/mL (+119%) on Day 22 (200 mg bid), 2.67 μg/mL (+94%) on Day 29 (100 mg bid), and 1.22 μg/mL (−12%) at ESV, respectively. In patients on carbamazepine and valproate, carbamazepine epoxide increased from 1.98 μg/mL at baseline to 2.72 μg/mL (+37%), 3.70 μg/mL (+87%), 4.43 μg/mL (+124%), 3.11 μg/mL (+57%), and 1.94 μg/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.ConclusionsCarbamazepine epoxide plasma concentrations were approximately doubled by brivaracetam 100 or 200 mg bid. Data are consistent with a dose-dependent and reversible inhibition of epoxide hydrolase by brivaracetam. Carbamazepine epoxide was approximately 0.7 μg/mL higher in presence of valproate. There is no need to limit brivaracetam dosing when used concomitantly with carbamazepine.