Fluconazole Dosing for the Prevention of Candida spp. Infections in Hemato-Oncologic Pediatric Patients: Population Pharmacokinetic Modeling and Probability of Target Attainment Simulations.

Objectives

A population pharmacokinetic (popPK) model was used to evaluate fluconazole dosing regimens for Candida spp. prophylaxis in hemato-oncologic pediatric patients.

Methods

Data were collected from patients receiving 3-12 mg/kg of fluconazole once daily as a 0.5 or 1 h infusion. Fluconazole concentrations were determined using a validated HPLC-UV method. The popPK model employed non-linear mixed effects modeling using the FOCEI algorithm implemented in nlmixr2. Monte Carlo simulations and probability of target attainment (PTA) analysis were performed in the rxode2 package to investigate dosing recommendations.

Results

Concentration time data from nine patients, aged 7 months to 18 years, with 35 samples, were described by a one-compartment model with first-order elimination and allometric scaling of body weight. Assuming a Candida spp. MIC = 2 mg/L and the ratio of the area under the unbound concentration-time curve at a steady state to the MIC (fAUC/MIC) ≥ 100 as the pharmacokinetic/pharmacodynamic (PK/PD) target, the standard dosing regimens reported in the Summary of Product Characteristics (SmPC) did not achieve the target for patients treated with doses < 6 mg/kg.

Conclusions

Hemato-oncologic pediatric patients require increased fluconazole doses to attain therapeutic efficacy. These results warrant clinical validation and should be confirmed by assessing a larger number of patients.