title: Pharmacokinetic variability, efficacy and tolerability of eslicarbazepine acetate-A national approach to the evaluation of therapeutic drug monitoring data and clinical outcome.
abstract: Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED), still insufficiently studied regarding pharmacokinetic variability, efficacy and tolerability. The purpose of this study was to evaluate therapeutic drug monitoring (TDM) data in Norway and relate pharmacokinetic variability to clinical efficacy and tolerability in a long-term clinical setting in patients with refractory epilepsy.
  
  
  
  This retrospective observational study included TDM-data from the main laboratories and population data from the Norwegian Prescription Database in Norway, in addition to clinical data from medical records of adult patients using ESL for up to three years, whenever possible.
  
  
  
  TDM-data from 168 patients were utilized for assessment of pharmacokinetic variability, consisting of 71% of the total number of patients in Norway using ESL, 2011-14. Median daily dose of ESL was 800mg (range 400-1600mg), and median serum concentration of ESL was 53μmol/L (range 13-132μmol/L). Inter-patient variability of ESL was extensive, with 25-fold variability in concentration/dose ratios. Additional clinical data were available from 104 adult patients out of the 168, all with drug resistant focal epilepsy. After 1, 2 and 3 years follow-up, the retention rate of ESL was 83%, 72% and 64%, respectively. ESL was generally well tolerated as add-on treatment, but sedation, cognitive impairment and hyponatremia were reported. Hyponatremia (sodium <137mmol/L) was present in 36% of the patients, and lead to discontinuation in three.
  
  
  
  Pharmacokinetic variability of ESL was extensive and the demonstration of usefulness of TDM requires further studies. In patients with drug resistant focal Epilepsy, the high retention rate indicated good efficacy and tolerability. Hyponatremia was observed in one third of the patients. The present results point to a need for individualization of treatment and TDM may be useful.
authors.affiliation: The National Center for Epilepsy, Sandvika, Oslo University Hospital, Oslo, Norway. Electronic address: torle-sv@online.no.
authors.forename: Torleiv
authors.initials: T
authors.lastname: Svendsen
authors.affiliation: Department of Neurology and Clinical Neurophysiology, St. Olav's University Hospital, Trondheim, Norway; Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Eylert
authors.initials: E
authors.lastname: Brodtkorb
authors.affiliation: Dept. of Clinical Pharmacology, St. Olav's University Hospital, Trondheim, Norway; Dept. of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Reimers
authors.affiliation: Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Molden
authors.affiliation: The National Center for Epilepsy, Sandvika, Oslo University Hospital, Oslo, Norway.
authors.forename: Erik
authors.initials: E
authors.lastname: Sætre
authors.affiliation: The National Center for Epilepsy, Sandvika, Oslo University Hospital, Oslo, Norway; Dept. of Pharmacology, Oslo University Hospital, Oslo, Norway.
authors.forename: Svein I
authors.initials: SI
authors.lastname: Johannessen
authors.affiliation: The National Center for Epilepsy, Sandvika, Oslo University Hospital, Oslo, Norway; Dept. of Pharmacology, Oslo University Hospital, Oslo, Norway; Programme for Pharmacy, Dept. of Life Sciences and Health, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Johannessen Landmark
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003984:Dibenzazepines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016903:Drug Monitoring; D000069279:Drug Resistant Epilepsy / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007010:Hyponatremia / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009664:Norway; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D003984:Dibenzazepines; C416835:eslicarbazepine acetate
keywords: Antiepileptic drugs; Epilepsy; Eslicarbazepine acetate; Pharmacokinetic variability; Retention rate; Therapeutic drug monitoring (TDM)