title: Pharmacokinetic interaction of brivaracetam on carbamazepine in adult patients with epilepsy, with and without valproate co-administration.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: UCB Pharma, Braine l'Alleud, Belgium. Electronic address: Armel.Stockis@ucb.com.
authors.forename: Armel
authors.initials: A
authors.lastname: Stockis
authors.affiliation: UCB Pharma, Braine l'Alleud, Belgium.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Sargentini-Maier
authors.affiliation: Epilepsy Unit West Glasgow, ACH-Yorkhill, Glasgow, Scotland, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Brodie
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002220:Carbamazepine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy*; D004851:Epoxide Hydrolases / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D014635:Valproic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D015415:Biomarkers; D011760:Pyrrolidinones; D002220:Carbamazepine; D014635:Valproic Acid; D004851:Epoxide Hydrolases; C482793:brivaracetam
keywords: Brivaracetam; Carbamazepine; Carbamazepine epoxide; Drug interaction; Pharmacokinetics; Valproate