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Multiplex Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneous Quantification in Human Plasma of Fluconazole, Itraconazole, Hydroxyitraconazole, Posaconazole, Voriconazole, Voriconazole-N-Oxide, Anidulafungin, and Caspofungin

  • Decosterd, Laurent Arthur Division of Clinical Pharmacology, Department of Medicine
  • Rochat, Bertrand Quantitative Mass Spectrometry Facility, Department of Research & Training, Faculty of Biology and Medicine
  • Pesse, Benoît Infectious Diseases Service, Department of Medicine
  • Mercier, Thomas Division of Clinical Pharmacology, Department of Medicine
  • Tissot, Frédéric Infectious Diseases Service, Department of Medicine
  • Widmer, Nicolas Division of Clinical Pharmacology, Department of Medicine
  • Bille, Jacques Institute of Microbiology, Department of Laboratory Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
  • Calandra, Thierry Infectious Diseases Service, Department of Medicine
  • Zanolari, Boris Division of Clinical Pharmacology, Department of Medicine
  • Marchetti, Oscar Infectious Diseases Service, Department of Medicine
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  • Antimicrobial Agents and Chemotherapy. - American Society for Microbiology. - 2010, vol. 54, no. 12, p. 5303-5315
Pharmacology (medical)
Pharmacology
Infectious Diseases
English ABSTRACT
Therapeutic drug monitoring (TDM) may contribute to optimizing the efficacy and safety of antifungal therapy because of the large variability in drug pharmacokinetics. Rapid, sensitive, and selective laboratory methods are needed for efficient TDM. Quantification of several antifungals in a single analytical run may best fulfill these requirements. We therefore developed a multiplex ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method requiring 100 μl of plasma for simultaneous quantification within 7 min of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, caspofungin, and anidulafungin. Protein precipitation with acetonitrile was used in a single extraction procedure for eight analytes. After reverse-phase chromatographic separation, antifungals were quantified by electrospray ionization-triple-quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. Deuterated isotopic compounds of azole antifungals were used as internal standards. The method was validated based on FDA recommendations, including assessment of extraction yields, matrix effect variability (<9.2%), and analytical recovery (80.1 to 107%). The method is sensitive (lower limits of azole quantification, 0.01 to 0.1 μg/ml; those of echinocandin quantification, 0.06 to 0.1 μg/ml), accurate (intra- and interassay biases of −9.9 to +5% and −4.0 to +8.8%, respectively), and precise (intra- and interassay coefficients of variation of 1.2 to 11.1% and 1.2 to 8.9%, respectively) over clinical concentration ranges (upper limits of quantification, 5 to 50 μg/ml). Thus, we developed a simple, rapid, and robust multiplex UPLC-MS/MS assay for simultaneous quantification of plasma concentrations of six antifungals and two metabolites. This offers, by optimized and cost-effective lab resource utilization, an efficient tool for daily routine TDM aimed at maximizing the real-time efficacy and safety of different recommended single-drug antifungal regimens and combination salvage therapies, as well as a tool for clinical research.
Language
  • English
Open access status
bronze
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https://sonar.ch/global/documents/113750
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