title: Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects.
abstract: OBJECTIVE
  To investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of simvastatin (SMV), a known CYP3A4 substrate, in healthy subjects.
  
  
  METHODS
  Single centre, two-way cross-over, randomized, open-label study in 24 healthy volunteers. The volunteers received an oral single-dose of SMV 80mg on two occasions (once administered alone and once after treatment with an oral once-daily dose of 800mg of ESL for 14 days), separated by a wash-out period of 3 weeks or more. The analysis of variance (ANOVA) was used to test for differences between Test (SMV under co-administration with ESL) and Reference (SMV administered alone) treatments for AUC0-∞, AUC0-t and Cmax of SMV and SMV-acid.
  
  
  RESULTS
  Mean systemic exposure (AUC) measurements for both SMV and SMV-β-hydroxyacid (SMV-acid) were up to 54% lower during ESL use. The Test/Reference geometric mean ratios (GMR) (90% CI) for the AUC0-t of SMV and SMV-acid were 46% (38%; 55%) and 49% (44%; 55%), respectively. Mean peak concentrations (Cmax) of both SMV and SMV-acid were reduced by 60% and 41%, respectively, when SMV was administered with ESL.
  
  
  CONCLUSIONS
  A significant effect of repeated ESL administration on the pharmacokinetics of SMV and its metabolite SMV-acid was observed. Therefore, dose adjustment of SMV may be required when used concomitantly with ESL, if a clinically significant change in lipids is noted.
authors.affiliation: Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
authors.forename: Amílcar
authors.initials: A
authors.lastname: Falcão
authors.forename: Roberto
authors.initials: R
authors.lastname: Pinto
authors.forename: Teresa
authors.initials: T
authors.lastname: Nunes
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003984:Dibenzazepines / Q000009:adverse effects / Q000494:pharmacology*; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000097:blood / Q000493:pharmacokinetics*; D061567:Voltage-Gated Sodium Channel Blockers / Q000009:adverse effects* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D003984:Dibenzazepines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D061567:Voltage-Gated Sodium Channel Blockers; D019821:Simvastatin; C416835:eslicarbazepine acetate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Antiepileptic drugs; Eslicarbazepine acetate; Healthy subjects; Pharmacokinetics; Simvastatin