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

Abstract

Background: The efficacy of fluconazole is related to the area under the plasma concentration-time curve over the minimum inhibitory concentration of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole and therefore dosing adjustments might be needed. Objective: The aim of this study was to evaluate variability in fluconazole drug concentration in ICU patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. Methods: 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 nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Results: 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 L (SD 19.81) and the mean clearance was 0.767 L/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 Cmin. Conclusion: Substantial variability in fluconazole plasma concentrations in critically-ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin TDM guided dosing can be used to optimize therapy in critically ill patients.

Pharmacokinetic Variability and Target Attainment of Fluconazole in Critically Ill Patients

“…The importance of the fluconazole dose was reported in the DALI study, in which a maintenance dose of 6 mg/kg instead of the fixed 400 mg dose was advocated [8]. Moreover, our study confirmed that renal function is an important driver of fluconazole exposure, which was also observed in earlier reports [10]. A daily dose of 600 mg for patients with adequate renal function, and 800 mg for patients undergoing CRRT, was previously recommended based on a pharmacokinetic evaluation of 19 patients [9].…”

“…Another pharmacokinetic (PK) study (n = 19) confirmed highly variable fluconazole clearance and the need for higher-than-standard doses, i.e., >400 mg once daily, in critically ill patients in order to attain the predefined exposure targets-especially in patients with an adequate to augmented renal clearance or CRRT [9]. A recent PK study (n = 49) reported substantial variability in fluconazole plasma concentrations in critically ill patients, with underexposure detected in the majority of them [10].…”

“…In the DALI study, administering a median [IQR] dose of 400 (200-400) mg or 4.9 (2.3-5.0) mg/kg resulted in a mean fluconazole C min of 14 mg/L [8]. Boonstra et al reported C min values of 6.4 mg/L and 13.3 mg/L on day 1 and 5 of treatment, respectively, in 21 critically ill patients treated with 400 mg fluconazole 24 h after a loading dose of 800 mg [10]. Our median trough concentration was higher than that reported in all of the above studies.…”

“…The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommends a free area under the concentration-time curve above the minimum inhibitory concentration (f AUC/MIC) of at least 100 [20]. Studies have shown that AUC correlates well with plasma trough concentration, which is more practical to use in clinical settings [10,21]. In cases of Candida spp.…”

“…In cases of Candida spp. with a MIC value of up to 4 mg/L, a f AUC of 400 is targeted, corresponding to trough concentrations of around 10-15 mg/L [10,22].…”