Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients

Abstract

The efficacy of fluconazole is related to the area under the plasma concentration-time curve (AUC) over the MIC of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole, and therefore dosing adjustments might be needed. The aim of this study was to evaluate variability in fluconazole drug concentration in intensive care unit (ICU) patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with a nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 liters (standard deviation [SD], 19.81) and the mean clearance was 0.767 liters/h (SD, 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the trough concentration (Cmin). Substantial variability in fluconazole plasma concentrations in critically ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin therapeutic drug monitoring (TDM)-guided dosing can be used to optimize therapy in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02491151.).

Keywords: critically ill; fluconazole; invasive candidiasis; pharmacokinetics.

Copyright © 2021 American Society for Microbiology.

Figures

FIG 1

(A) The population-predicted versus observed goodness-of-fit plots for the final one-compartment model. (B) The individual predicted versus observed goodness-of-fit plots for the final one-compartment model.

FIG 2

The Bayesian posterior predictions for the external data set.

FIG 3

(A) The PTAs for an fAUC/MIC target of 100 for the third day of therapy for fixed dosing. The x axis presents the MIC targets, and the y axis presents the proportion of success. (B) The PTAs for an fAUC/MIC target of 100 for the third day of therapy for weight-based dosing. The x axis presents the MIC targets, and the y axis presents the proportion of success.

FIG 4

(A) The fluconazole exposure after a loading dose correlated with the trough concentration. (B) The fluconazole exposure after a loading dose correlated with the dose. (C) The fluconazole exposure after 5 days of dosing correlated with the trough concentration. (D) The fluconazole exposure after 5 days of dosing correlated with the dose.