title: Brivaracetam and carbamazepine interaction in healthy subjects and in vitro.
abstract: This phase I, open-label study investigated the effects of steady-state brivaracetam administration on steady-state pharmacokinetics of carbamazepine, and steady-state carbamazepine administration on single-dose and steady-state pharmacokinetics of brivaracetam, in 14 healthy participants who received brivaracetam 200mg single doses on days 1 and 22, and 200mg twice daily (bid) on days 24-35; and were titrated to carbamazepine 300mg bid on days 4-35. Brivaracetam did not significantly alter carbamazepine area under the plasma concentration-time curve (AUC) over a dosing interval, but resulted in a 2.6-fold increase in carbamazepine-epoxide. Carbamazepine decreased brivaracetam AUC by 29%, while hydroxy-brivaracetam metabolite was increased by 17%. Urinary 6β-hydroxycortisol/cortisol ratio was unchanged by brivaracetam, but was increased 3-fold by carbamazepine. In vitro hydrolysis of carbamazepine-epoxide in human hepatocytes was inhibited by brivaracetam, with an IC50 of 8.2μM. Brivaracetam 200mg bid was predicted to increase carbamazepine-epoxide by 2.3-fold, in close agreement with the observed value. In conclusion, brivaracetam did not modify carbamazepine exposure but increased carbamazepine-epoxide. Carbamazepine modestly decreased brivaracetam exposure and increased oxidative metabolism.
authors.affiliation: UCB Pharma, Clinical Pharmacology, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium. Electronic address: Armel.Stockis@ucb.com.
authors.forename: Armel
authors.initials: A
authors.lastname: Stockis
authors.affiliation: UCB Pharma, Investigative ADME, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium.
authors.forename: Hugues
authors.initials: H
authors.lastname: Chanteux
authors.affiliation: UCB Pharma, Investigative ADME, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Rosa
authors.affiliation: Medeval Ltd, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Rolan
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000097:blood* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002220:Carbamazepine / Q000097:blood* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004851:Epoxide Hydrolases / Q000378:metabolism; D005500:Follow-Up Studies; D064368:Healthy Volunteers; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000097:blood* / Q000493:pharmacokinetics; D018709:Statistics, Nonparametric; D013997:Time Factors; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D011760:Pyrrolidinones; D002220:Carbamazepine; C001380:6 beta-hydroxycortisol; D004851:Epoxide Hydrolases; C482793:brivaracetam; D006854:Hydrocortisone
keywords: Brivaracetam; Carbamazepine; Epilepsy; Interaction; Pharmacokinetics; Synaptic vesicle protein 2A