Variability of Voriconazole Plasma Levels Measured by New High-Performance Liquid Chromatography and Bioassay Methods
Author:
Pascual A, Nieth V, Calandra T, Bille J, Bolay S, Decosterd LA, Buclin T, Majcherczyk PA, Sanglard D, Marchetti O
Date: 4 December 2006
Abstract:
Voriconazole is a broad-spectrum antifungal triazole with non-linear pharmacokinetics. The utility of measurement of voriconazole blood levels for optimizing therapy is matter of debate. Available high-performance liquid chromatography (HPLC) and bioassay methods are technically complex, time demanding 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/Delta,cdr2Delta/Delta,flu1Delta/Delta,mdr1Delta/Delta) and calcineurin subunit A (cnaDelta/Delta) was used for bioassay. Mean intra-/inter-run accuracy over the VRC concentration range 0.25-16 mg/L was 93.7%+/-5.0/96.5%+/-2.4 (HPLC) and 94.9%+/-6.1/94.7%+/-3.3 (bioassay). Mean intra-/inter-run coefficient of variation was 5.2%+/-1.5/5.4%+/-0.9 and 6.5%+/-2.5/4.0%+/-1.6, respectively. The coefficient of concordance between HPLC and bioassay was 0.96. Sequential measurements in ten patients with invasive mycoses showed important inter- and intra-individual variations of estimated voriconazole AUC: median 43.9 mg.h/L (range 12.9-71.1) on first and 27.4 (range 2.9-93.1) on 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 VRC AUC (from 71.1 to 93.1) was observed. VRC AUC decreased (from 12.9 to 2.9 mg.h/L) 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.
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