title: Pharmacokinetics of eslicarbazepine acetate at steady-state in adults with partial-onset seizures.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics of eslicarbazepine acetate (ESL) at steady-state in adults with partial-onset seizures who have taken ESL for at least 1 year with one or two concomitant antiepileptic drugs (AEDs).
  
  
  METHODS
  Blood samples for the pharmacokinetic assessment were taken at pre-dose, and 1, 2, 3, 4, 6, 8, 12 and 24h post-dose at steady-state in 51 patients stabilised on chronic (beyond 1 year) treatment with ESL 400mg (n=7), 800mg (n=26) or 1200mg (n=18) once-daily. Most patients (n=29, 56.9%) were receiving 2 concomitant AEDs, and most frequent co-medications were carbamazepine (n=34, 66.7%) and valproic acid (n=19, 37.3%). Plasma concentrations of ESL and its metabolites eslicarbazepine, R-licarbazepine and oxcarbazepine (OXC) were determined by a validated chiral method using liquid chromatography coupled to mass spectrometry.
  
  
  RESULTS
  Similarly to earlier findings in healthy subjects, plasma ESL concentrations were consistently below the lower limit of quantification (50ng/mL). The major compound in plasma was the active metabolite eslicarbazepine, which reached maximum concentrations (C(max)) 2h post-dose; thereafter, its plasma concentrations declined with a mean apparent half-life of 13, 14, and 20h in patients receiving ESL doses of 400, 800, and 1200mg once daily, respectively. Eslicarbazepine C(max) were 9.7, 15.5 and 23.0μg/mL, and areas under the plasma concentration-time curve over the dosing interval (AUC(0-24)) were 132.5, 205.4 and 336.1μgh/mL in patients receiving ESL doses of 400, 800 and 1200mg once-daily, respectively. Eslicarbazepine main pharmacokinetic parameters (C(max) and AUC(0-24)) were dose-proportional. R-licarbazepine and OXC were minor metabolites.
  
  
  CONCLUSIONS
  Following once-daily oral administration of ESL 400mg, 800mg and 1200mg to epilepsy patients treated concomitantly with one or two other AEDs, ESL was rapidly converted to eslicarbazepine, which was the primary active compound found in plasma. Systemic exposure to eslicarbazepine was dose-proportional.
authors.affiliation: Department of Internal Medicine and Therapeutics, University of Pavia, and Clinical Trial Center, National Institute of Neurology IRCCS C Mondino Foundation, Pavia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Perucca
authors.forename: C
authors.initials: C
authors.lastname: Elger
authors.forename: P
authors.initials: P
authors.lastname: Halász
authors.forename: A
authors.initials: A
authors.lastname: Falcão
authors.forename: L
authors.initials: L
authors.lastname: Almeida
authors.forename: P
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000097:blood* / Q000737:chemistry / Q000627:therapeutic use*; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use; D003984:Dibenzazepines / Q000097:blood* / Q000737:chemistry / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D000078330:Oxcarbazepine; D012640:Seizures / Q000097:blood* / Q000188:drug therapy*; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D003984:Dibenzazepines; D002220:Carbamazepine; C416835:eslicarbazepine acetate; D000078330:Oxcarbazepine; C428744:10,11-dihydro-10-hydroxy-5H-dibenz(b,f)azepine-5-carboxamide