Saliva for TDM of antifungal drugs: voriconazole model

Aims. Therapeutic drug monitoring (TDM) is recommended for many antifungal drugs. Saliva sampling is a non-invasive alternative to plasma sampling. However, no clinically validated
saliva models available. This study firstly aims 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.

Methods. Databases were searched up to July 2019 on PubMed® and Embase.® Fourteen studies were included in the systematic review of fluconazole, voriconazole, itraconazole, and ketoconazole. No studies were found for isavuconazole, posaconazole, flucytosine, amphotericin B, caspofungin, micafungin or anidulafungin.

Results. Fluconazole and voriconazole showed 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 conducted on voriconazole using Nonlinear Mixed Effects Modelling (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, modelled 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.

Conclusion. The developed saliva model characterised salivary distribution of voriconazole and provides a promising framework to facilitate saliva-based TDM of voriconazole.