title: Investigation of Saliva as an Alternative to Plasma Monitoring of Voriconazole.
abstract: OBJECTIVE
  Therapeutic drug monitoring (TDM) of voriconazole is increasingly being implemented in clinical practice. However, as blood sampling can be difficult in paediatric and ambulatory patients, a non-invasive technique for TDM is desirable. The aim of this study was to compare the pharmacokinetics of voriconazole in saliva with the pharmacokinetics of unbound and total voriconazole in plasma in order to clinically validate saliva as an alternative to plasma in voriconazole TDM.
  
  
  METHODS
  In this pharmacokinetic study, paired plasma and saliva samples were taken at steady state in adult haematology and pneumology patients treated with voriconazole. Unbound and bound plasma voriconazole concentrations were separated using high-throughput equilibrium dialysis. Voriconazole concentrations were determined with liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using log-linear regression.
  
  
  RESULTS
  Sixty-three paired samples were obtained from ten patients (seven haematology and three pneumology patients). Pearson's correlation coefficients (R values) for saliva versus unbound and total plasma voriconazole concentrations showed a very strong correlation, with values of 0.970 (p < 0.001) and 0.891 (p < 0.001), respectively. Linear mixed modelling revealed strong agreement between voriconazole concentrations in saliva and unbound plasma voriconazole concentrations, with a mean bias of -0.03 (95 % confidence interval -0.14 to 0.09; p = 0.60). For total concentrations below 10 mg/L, the mean ratio of saliva to total plasma voriconazole concentrations was 0.51 ± 0.08 (n = 63), which did not differ significantly (p = 0.76) from the unbound fraction of voriconazole in plasma of 0.49 ± 0.03 (n = 36).
  
  
  CONCLUSIONS
  Saliva can serve as a reliable alternative to plasma in voriconazole TDM, and it can easily be implemented in clinical practice.
authors.affiliation: Clinical Pharmacology and Pharmacotherapy, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000, Leuven, Belgium. kim_vanstraelen@hotmail.com.
authors.forename: Kim
authors.initials: K
authors.lastname: Vanstraelen
authors.affiliation: Acute Leukaemia and Stem Cell Transplantation Unit, Clinical Department of Haematology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.affiliation: Clinical Department of Laboratory Medicine, Department of Microbiology and Immunology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Lagrou
authors.affiliation: Laboratory of Nephrology and Renal Transplantation, KU Leuven Department of Microbiology and Immunology, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Henriette
authors.initials: H
authors.lastname: de Loor
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Mols
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Cystic Fibrosis Clinic, Research Group GRON, Universitair Ziekenhuis Brussel (UZ Brussel); Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Malfroot
authors.affiliation: Clinical Pharmacology and Pharmacotherapy, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Isabel
authors.initials: I
authors.lastname: Spriet
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001228:Aspergillosis / Q000188:drug therapy*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012463:Saliva / Q000737:chemistry* / Q000378:metabolism; D065819:Voriconazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D065819:Voriconazole