Saliva for Precision Dosing of Antifungal Drugs: Saliva Population PK Model for Voriconazole Based on a Systematic Review

Hannah Yejin Kim; Anne-Grete Märtson; Erwin Dreesen; Isabel Spriet; Sebastian G Wicha; Andrew J McLachlan; Jan-Willem Alffenaar

doi:10.3389/fphar.2020.00894

Saliva for Precision Dosing of Antifungal Drugs: Saliva Population PK Model for Voriconazole Based on a Systematic Review

Front Pharmacol. 2020 Jun 12:11:894. doi: 10.3389/fphar.2020.00894. eCollection 2020.

Authors

Hannah Yejin Kim^{1

2

3}, Anne-Grete Märtson⁴, Erwin Dreesen⁵, Isabel Spriet^{5

6}, Sebastian G Wicha⁷, Andrew J McLachlan¹, Jan-Willem Alffenaar^{1

2

3}

Affiliations

¹ Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
² Department of Pharmacy, Westmead Hospital, Westmead, NSW, Australia.
³ Marie Bashir Institute of Infectious Diseases and Biosecurity, The University of Sydney, Camperdown, NSW, Australia.
⁴ University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, Netherlands.
⁵ Department of Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy, KU Leuven, Leuven, Belgium.
⁶ Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.
⁷ Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany.

Abstract

Precision dosing for many antifungal drugs is now recommended. Saliva sampling is considered as a non-invasive alternative to plasma sampling for therapeutic drug monitoring (TDM). However, there are currently no clinically validated saliva models available. The aim of this study is firstly, to conduct a systematic review to evaluate the evidence supporting saliva-based TDM for azoles, echinocandins, amphotericin B, and flucytosine. The second aim is to develop a saliva population pharmacokinetic (PK) model for eligible drugs, based on the evidence. Databases were searched up to July 2019 on PubMed^® and Embase^®, and 14 studies were included in the systematic review for fluconazole, voriconazole, itraconazole, and ketoconazole. No studies were identified for isavuconazole, posaconazole, flucytosine, amphotericin B, caspofungin, micafungin, or anidulafungin. Fluconazole and voriconazole demonstrated a good saliva penetration with an average S/P ratio of 1.21 (± 0.31) for fluconazole and 0.56 (± 0.18) for voriconazole, both with strong correlation (r = 0.89-0.98). Based on the evidence for TDM and available data, population PK analysis was performed on voriconazole using Nonlinear Mixed Effects Modeling (NONMEM 7.4). 137 voriconazole plasma and saliva concentrations from 11 patients (10 adults, 1 child) were obtained from the authors of the included study. Voriconazole pharmacokinetics was best described by one-compartment PK model with first-order absorption, parameterized by clearance of 4.56 L/h (36.9% CV), volume of distribution of 60.7 L, absorption rate constant of 0.858 (fixed), and bioavailability of 0.849. Kinetics of the voriconazole distribution from plasma to saliva was identical to the plasma kinetics, but the extent of distribution was lower, modeled by a scale factor of 0.5 (4% CV). A proportional error model best accounted for the residual variability. The visual and simulation-based model diagnostics confirmed a good predictive performance of the saliva model. The developed saliva model provides a promising framework to facilitate saliva-based precision dosing of voriconazole.

Keywords: antifungal drug; oral fluid; population pharmacokinetic model; precision dosing; saliva; therapeutic drug monitoring; voriconazole.