Pharmacokinetic Evaluation of Voriconazole Treatment in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration

Introduction: 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 AUC(0-12), 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.