title: Population Pharmacokinetics of High-Dose Oxazepam in Alcohol-Dependent Patients: Is There a Risk of Accumulation?
abstract: BACKGROUND
  According to the guidelines, benzodiazepines with a short half-life are the reference medication to treat alcohol withdrawal syndrome. The doses of oxazepam used in this population may reach up to 300 mg per day, significantly higher than usual doses. Its use in these patients deserves further information to confirm that the half-life remains constant and that no accumulation appears. The objective of this study was to investigate the pharmacokinetics of high doses of oxazepam in alcohol-dependent patients treated for alcohol withdrawal syndrome.
  
  
  METHODS
  Overall, 63 outpatients [weight, 71.1 kg (45.0-118.0); age, 47.6 years (31-67)] followed in the addictology unit, were studied. Total mean dose of 96.0 mg per day (range, 20-300 mg/d) was administered by oral route. Therapeutic drug monitoring allowed the measurement of 96 plasma concentrations. The following covariates were evaluated: demographic data (age, body weight, height, gender) and biological data (creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase). Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model.
  
  
  RESULTS
  Data were modeled with a 1-compartment pharmacokinetic model. The population typical mean 90% confidence interval values for clearance, apparent volume of distribution (V), and duration of absorption (D1) were 6.8 L/h (range, 3.9-8.0 L/h), 159 L (range, 98.0-282 L), and 2 hours (fixed), respectively. The interindividual variability of clearance and V, and residual variability (90% confidence interval) were 74% (44%-96%), 69% (40%-89%), and 32% (20%-41%), respectively. The elimination half-life was 16 hours (range, 3-42 hours).
  
  
  CONCLUSIONS
  Oxazepam exhibited a linear pharmacokinetics with a proportional relationship from 20 to 300 mg per day, the dose range currently used in alcohol-dependent patients treated for alcohol withdrawal syndrome. We did not find any evidence of drug accumulation with these doses.
authors.affiliation: *Department of Addictology, Allauch Hospital Center; †Aix-Marseille University, INSERM U912 (SESSTIM); APHM, Hôpital Sainte Marguerite, Service de Pharmacologie clinique, CAP-TV; and ‡Department of Clinical Pharmacology, Timone University Hospital; APHM, Hôpital Sainte Marguerite, Service de Pharmacologie clinique, CAP-TV, 13,274 Marseille, France.
authors.forename: Bruce
authors.initials: B
authors.lastname: Imbert
authors.forename: Amélie
authors.initials: A
authors.lastname: Marsot
authors.forename: Natalia
authors.initials: N
authors.lastname: Liachenko
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simon
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000097:blood / Q000188:drug therapy*; D001835:Body Weight / Q000187:drug effects; D016903:Drug Monitoring / Q000379:methods; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010076:Oxazepam / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D012306:Risk; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000188:drug therapy*
chemical_list: D000431:Ethanol; D010076:Oxazepam