Therapeutic drug monitoring of voriconazole: validation of a novel ARK™ immunoassay and comparison with ultra-high performance liquid chromatography.

Abstract

Voriconazole (VRC) is a second-generation triazole licensed to treat patients with invasive aspergillosis, invasive candiadiasis caused by Candida species with reduced susceptibility to fluconazole, and serious infections caused by Scedosporium and Fusarium species [1, 2]. Recently, prophylaxis of invasive fungal infections (IFIs) in high risk allogeneic hematopoietic stem cell transplant recipients was added as a new indication for VRC [3]. According to the British Society for Medical Microbiology (BSMM), trough concentrations > 1 mg/L and < 4–6 mg/L are required to maximize efficacy and to minimize drugrelated toxicity [4]. In patients treated for IFIs with the recommended oral/intravenous VRC dosage regimen, large interand intra-individual variability has been found in VRC trough plasma concentrations, ranging from undetectable concentrations to 11 mg/L [5]. Oral bioavailability is a major determinant of variability of VRC plasma concentrations [6]. In healthy individuals, oral bioavailability is reported to be high, approximately 96%, when administered in a fasting state (1 h before/after meal) [2]. However, in patients, oral bioavailability might be much lower, as these patients are frequently suffering from gastro-intestinal complications [6, 7]. Other factors that contribute to the variability in VRC plasma concentrations are the Michaelis-Menten (non-linear) pharmacokinetics of VRC, polymorphisms of the gene encoding the CYP2C19 enzyme, drug-drug interactions, liver disease and age [4]. The large variability in VRC plasma concentrations together with the narrow therapeutic window for treating patients with IFIs, makes individualized dosing adjustments based on therapeutic drug monitoring (TDM) of VRC necessary to optimize therapeutic response and to minimize the probability of neurotoxicity [6]. According to the BSMM, VRC plasma concentrations should be measured in the first 5 days of therapy and regularly thereafter [4]. In Table 1, an overview is given of the analytical methods that are suitable for measuring VRC in plasma, including bioassays [8–11], HPLC [12–19] and LC-MSMS [20– 29] methods. Currently, chromatographic methods are predominantly used, as can also be derived from proficiency testing results [30]. These techniques are accurate, precise and allow the simultaneous analysis of multiple antifungal drugs. However, these methods also include some disadvantages, such as the limited availability of chromatographic instruments in the core clinical laboratory, the need for skilled laboratory technicians, the use of (sometimes) time consuming sample preparation steps and the need aCurrent address: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium *Corresponding author: Veronique Stove, Department of Laboratory Medicine, Ghent University Hospital, De Pintelaan 185 (2P8), 9000 Ghent, Belgium, Phone: +32 9 3325871, Fax: +32 3324985, E-mail: Veronique.Stove@UGent.be Lien Cattoir and Alain G. Verstraete: Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium; and Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Gregoire Fauvarque: Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium Simon Degandt and Timothy Ghys: Clinical Laboratory, General Hospital Sint-Lucas Ghent, Ghent, Belgium