Variability of Voriconazole Plasma Levels Measured by New High-Performance Liquid Chromatography

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-hypersuscep-tible Candida albicans mutant lacking multidrug efflux transporters (cdr1/cdr1, cdr2/cdr2, flu1/flu1, and mdr1/mdr1) and calcineurin subunit A (cna/cna) 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 · h/liter (range, 12.9 to 71.1) on the first and 27.4 mg · h/liter (range, 2.9 to 93.1) on the last day of therapy. During therapy, AUC decreased in five patients, increased i