title: Pharmacokinetic evaluation of voriconazole treatment in critically ill patients undergoing continuous venovenous hemofiltration.
abstract: BACKGROUND
  Voriconazole represents an essential part of antimicrobial therapy in critically ill patients. The aim of this study was to exclude a significant alteration in voriconazole pharmacokinetics in critically ill patients undergoing continuous venovenous hemofiltration (CVVH).
  
  
  METHODS
  Six patients dependent on CVVH with evidence of an invasive mycotic infection treated with intravenous voriconazole at the standard dosing regimen were investigated. The total serum concentration of voriconazole in arterial blood and the concentration in ultrafiltrate were measured by reverse-phase high-performance liquid chromatography with ultraviolet detection. The authors profiled a 5-point pharmacokinetic concentration-time curve during the 12-hour standard maintenance dosing interval and derived the basic pharmacokinetic parameters.
  
  
  RESULTS
  The serum voriconazole concentration did not decrease <1.0 mg/L at any time point, and the mean was 4.3 ± 2.6 mg/L and the median (range) 3.6 (9.0) mg/L. The sieving coefficient of the drug did not exceed 0.30 in any patient (0.22 ± 0.08). The mean serum AUC0-12, the mean total clearance, and the mean clearance via CVVH were 53.52 ± 29.97 mg·h/L [the median (range) of 57.74 (62.34) mg·h/L], 0.11 ± 0.07 L·h-1·kg-1, and 0.007 ± 0.003 L·h-1·kg-1, respectively. The clearance by the CVVH method ranged from 4% to 20% of the total drug clearance. The disposition of voriconazole was not compromised. The mean elimination half-life was 27.58 ± 35.82 hours [the median of 13.10 (92.21) hours], and the mean distribution volume value was 3.28 ± 3.10 L/kg [the median of 2.01 (8.10) L/kg]. Marked variability in serum concentrations, elimination half-life, distribution volume, and total clearance was seen. Half of the patients showed some drug accumulation.
  
  
  CONCLUSIONS
  The clearance of voriconazole by CVVH is not clinically significant. In view of this finding, voriconazole dose adjustment in patients undergoing the standard method of CVVH is not required. However, the observed potential for an unpredictable voriconazole accumulation suggests the usefulness for monitoring its levels in critically ill patients.
authors.affiliation: 1st Medical Department, ICU, Charles University Medical School and Teaching Hospital, Plzen, Czech Republic. radejj@fnplzen.cz
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Radej
authors.forename: Ales
authors.initials: A
authors.lastname: Krouzecky
authors.forename: Pavel
authors.initials: P
authors.lastname: Stehlik
authors.forename: Roman
authors.initials: R
authors.lastname: Sykora
authors.forename: Jiri
authors.initials: J
authors.lastname: Chvojka
authors.forename: Thomas
authors.initials: T
authors.lastname: Karvunidis
authors.forename: Ivan
authors.initials: I
authors.lastname: Novak
authors.forename: Martin
authors.initials: M
authors.lastname: Matejovic
mesh_terms: D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016638:Critical Illness; D016903:Drug Monitoring / Q000379:methods; D006207:Half-Life; D006440:Hemofiltration; D006801:Humans; D009181:Mycoses / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065819:Voriconazole
chemical_list: D000890:Anti-Infective Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole