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Investigation of Saliva as an Alternative to Plasma Monitoring of Voriconazole

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Abstract

Background and Objectives

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.

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Acknowledgments

We would like to thank Dr. Petra Schelstraete and her team from the University Hospital Ghent for their willingness to cooperate in this project, Ine Vercammen for helping with the patient enrolment, and Pfizer for providing the pure voriconazole substance.

Conflict of interest

K. Vanstraelen has received travel support from Gilead, MSD and Pfizer, and received lecture honoraria from Pfizer. J. Maertens has received research grants from Gilead, MSD, Pfizer and Astellas, received travel support from Gilead, MSD, Pfizer and Astellas, and received lecture honoraria from Gilead, MSD, Pfizer and Astellas. K. Lagrou has received research grants from Gilead, MSD and Pfizer, received travel support from Gilead, MSD and Pfizer, and received lecture honoraria from Gilead, MSD and Pfizer. A. Malfroot received research grants from Wyeth-Pfizer, Novartis and GSK, received lecture honoraria from Gilead, Wyeth-Pfizer, Forest and GSK, received travel support from Gilead, Novartis, Abbott and Pfizer, and participated in advisory boards for Wyeth-Pfizer and GSK. I. Spriet has received research grants from MSD and Pfizer, received travel support from Gilead, MSD and Pfizer, and received lecture honoraria from Gilead, MSD and Pfizer, and remaining authors have no conflict of interest to declare.

Ethical standards

This study (ClinicalTrials.gov study ID: NCT01418846) was conducted in accordance with the Declaration of Helsinki. Approval from the local ethics committees and written informed consent from each subject were obtained.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacotherapy, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000, Leuven, Belgium

    Kim Vanstraelen & Isabel Spriet

  2. Acute Leukaemia and Stem Cell Transplantation Unit, Clinical Department of Haematology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Johan Maertens

  3. Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000, Leuven, Belgium

    Patrick Augustijns, Raf Mols & Pieter Annaert

  4. Clinical Department of Laboratory Medicine, Department of Microbiology and Immunology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Katrien Lagrou

  5. Laboratory of Nephrology and Renal Transplantation, KU Leuven Department of Microbiology and Immunology, Herestraat 49, 3000, Leuven, Belgium

    Henriette de Loor

  6. Cystic Fibrosis Clinic, Research Group GRON, Universitair Ziekenhuis Brussel (UZ Brussel); Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium

    Anne Malfroot

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  1. Kim Vanstraelen
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Correspondence to Kim Vanstraelen.

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Vanstraelen, K., Maertens, J., Augustijns, P. et al. Investigation of Saliva as an Alternative to Plasma Monitoring of Voriconazole. Clin Pharmacokinet 54, 1151–1160 (2015). https://doi.org/10.1007/s40262-015-0269-z

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