title: Relationship between mono-hydroxy-carbazepine serum concentrations and adverse effects in patients on oxcarbazepine monotherapy.
abstract: OBJECTIVE
  To evaluate the relationship between serum concentrations of mono-hydroxy-carbazepine (MHD), the main metabolite of oxcarbazepine (OXC), and the occurrence of adverse effects (AE) in a large group of patients on OXC monotherapy.
  
  
  METHODS
  An antiepileptic drug (AED) therapeutic drug monitoring (TDM) database was analyzed especially with regard to OXC dosage, MHD serum concentration, and the occurrence of AE. In total, 893 blood samples of 442 patients were included in this retrospective study. The statistical evaluation was performed by means of Kaplan-Meier estimates, log-rank tests and generalized estimating equations (GEE).
  
  
  RESULTS
  At least one AE was reported in 78 (17.6%) of the 442 patients. At MHD serum concentrations of 30.0 μg/ml and 43.7 μg/ml and OXC dosages of 33.1 mg/kg and 62.3 mg/kg, 25% and 75% of patients, respectively, experienced at least one AE. Log-rank tests indicated that younger patients (<18 years) may be able to tolerate higher MHD serum levels (p = 0.006) and higher OXC dosages per body weight (p < 0.001) compared to adult patients (≥ 18 years). Furthermore, AEs occurred at higher body-weight adjusted OXC dosages of extended release formulations compared to immediate-release formulations (p = 0.010), whereas MHD serum levels at which AEs occurred did not differ significantly between formulations (p = 0.125). Multivariate GEE confirmed the results.
  
  
  CONCLUSIONS
  The occurrence of AEs is significantly (and non-linearly) dependent on MHD serum level, whereas the dependence of OXC dosage is less distinctive. But, tolerability of OXC seems to depend on age of the patients as well as on pharmaceutical formulation of OXC.
authors.affiliation: Epilepsiezentrum Bethel, Krankenhaus Mara gGmbH, D-33617 Bielefeld, Germany; Charité Universitätsmedizin Berlin, Institut für klinische Pharmakologie, D-10115 Berlin, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Sattler
authors.affiliation: Charité Universitätsmedizin Berlin, Institut für klinische Pharmakologie, D-10115 Berlin, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Schaefer
authors.affiliation: Gesellschaft für Epilepsieforschung, D-33617 Bielefeld, Germany. Electronic address: may_gfe@t-online.de.
authors.forename: Theodor W
authors.initials: TW
authors.lastname: May
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging; D000927:Anticonvulsants / Q000009:adverse effects* / Q000097:blood* / Q000627:therapeutic use; D002220:Carbamazepine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D002648:Child; D062313:Databases, Pharmaceutical; D016903:Drug Monitoring; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D000078330:Oxcarbazepine; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D000078330:Oxcarbazepine
keywords: Adverse effect; Antiepileptic drug; Mono-hydroxy-carbazepine; Monotherapy; Oxcarbazepine; Therapeutic drug monitoring