title: Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods.
abstract: Voriconazole (VRC) is a broad-spectrum antifungal triazole with nonlinear pharmacokinetics. The utility of measurement of voriconazole blood levels for optimizing therapy is a matter of debate. Available high-performance liquid chromatography (HPLC) and bioassay methods are technically complex, time-consuming, or have a narrow analytical range. Objectives of the present study were to develop new, simple analytical methods and to assess variability of voriconazole blood levels in patients with invasive mycoses. Acetonitrile precipitation, reverse-phase separation, and UV detection were used for HPLC. A voriconazole-hypersusceptible Candida albicans mutant lacking multidrug efflux transporters (cdr1Delta/cdr1Delta, cdr2Delta/cdr2Delta, flu1Delta/flu1Delta, and mdr1Delta/mdr1Delta) and calcineurin subunit A (cnaDelta/cnaDelta) was used for bioassay. Mean intra-/interrun accuracies over the VRC concentration range from 0.25 to 16 mg/liter were 93.7% +/- 5.0%/96.5% +/- 2.4% (HPLC) and 94.9% +/- 6.1%/94.7% +/- 3.3% (bioassay). Mean intra-/interrun coefficients of variation were 5.2% +/- 1.5%/5.4% +/- 0.9% and 6.5% +/- 2.5%/4.0% +/- 1.6% for HPLC and bioassay, respectively. The coefficient of concordance between HPLC and bioassay was 0.96. Sequential measurements in 10 patients with invasive mycoses showed important inter- and intraindividual variations of estimated voriconazole area under the concentration-time curve (AUC): median, 43.9 mg x h/liter (range, 12.9 to 71.1) on the first and 27.4 mg x h/liter (range, 2.9 to 93.1) on the last day of therapy. During therapy, AUC decreased in five patients, increased in three, and remained unchanged in two. A toxic encephalopathy probably related to the increase of the VRC AUC (from 71.1 to 93.1 mg x h/liter) was observed. The VRC AUC decreased (from 12.9 to 2.9 mg x h/liter) in a patient with persistent signs of invasive aspergillosis. These preliminary observations suggest that voriconazole over- or underexposure resulting from variability of blood levels might have clinical implications. Simple HPLC and bioassay methods offer new tools for monitoring voriconazole therapy.
authors.affiliation: Infectious Diseases Service, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.
authors.forename: Andres
authors.initials: A
authors.lastname: Pascual
authors.forename: Valérie
authors.initials: V
authors.lastname: Nieth
authors.forename: Thierry
authors.initials: T
authors.lastname: Calandra
authors.forename: Jacques
authors.initials: J
authors.lastname: Bille
authors.forename: Saskia
authors.initials: S
authors.lastname: Bolay
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Decosterd
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Paul A
authors.initials: PA
authors.lastname: Majcherczyk
authors.forename: Dominique
authors.initials: D
authors.lastname: Sanglard
authors.forename: Oscar
authors.initials: O
authors.lastname: Marchetti
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001681:Biological Assay / Q000379:methods; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015203:Reproducibility of Results; D013056:Spectrophotometry, Ultraviolet; D016896:Treatment Outcome; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole