title: Steady-state pharmacokinetics and metabolism of voriconazole in patients.
abstract: OBJECTIVE
  Voriconazole exhibits non-linear pharmacokinetics in adults and is said to be mainly metabolized by CYP2C19 and CYP3A4 to voriconazole-N-oxide. The aim of this study was to obtain data on steady-state pharmacokinetics after dosing for at least 14 days in patients taking additional medication and in vivo data on metabolites other than voriconazole-N-oxide.
  
  
  METHODS
  Thirty-one patients receiving voriconazole as regular therapeutic drug treatment during hospitalization participated in this prospective study. Pharmacokinetic profiles were obtained for the 12 h (dosing interval) after the first orally administered dose (400 mg) or (if possible and) after an orally administered maintenance dose (200 mg) following intake for at least 14 days (n = 14 after first dose; n = 23 after maintenance dose). Blood and urine samples were collected and the concentrations of voriconazole and three of its metabolites (the N-oxide, hydroxy-voriconazole and dihydroxy-voriconazole) were determined, as well as the CYP2C19 genotype of the patients. All other drugs taken by the participating patients were evaluated.
  
  
  RESULTS
  A high variability of exposure (AUC) after the first dose was slightly reduced during steady-state dosing for voriconazole (82% to 71%) and the N-oxide (86% to 56%), remained high for hydroxy-voriconazole (79%) and even increased for dihydroxy-voriconazole (97% to 127%). In 16 of the 22 steady-state patients, trough plasma concentrations were <2 μg/mL. N-oxide plasma concentrations during steady state stayed almost constant. Hydroxylations of voriconazole seem to be quantitatively more important in its metabolism than N-oxidation.
  
  
  CONCLUSIONS
  High variability in voriconazole exposure, as well as low steady-state trough plasma concentrations, suggest that the suggested steady-state dosage of 200 mg twice a day has to be increased to prevent disease progression. Therapeutic drug monitoring is probably necessary to optimize the voriconazole dose for individual patients.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Marcus J P
authors.initials: MJ
authors.lastname: Geist
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Egerer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D001711:Biotransformation; D006801:Humans; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole
keywords: dihydroxy-voriconazole; exposure variability; hydroxy-voriconazole; therapeutic drug monitoring; voriconazole-N-oxide