Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Abstract

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.

FIG 1

Goodness-of-fit plots for the base model. (A) Predicted versus observed concentrations (Conc). (B) Individual (Indiv) predicted versus observed concentrations. (C) Conditional weighted residuals (CWRES) versus population predictions. (D) Conditional weighted residuals versus time after dose. For panels A and B, the line of identity is included as a reference. For panels C and D, a solid line at y = 0 is included as a reference.

FIG 2

Visual predictive check of the final model for scheduled samples (A) and scavenged samples (B), displaying time after first dose.

FIG 3

Monte Carlo simulations of fluconazole given at 6 mg/kg intravenously (IV) twice weekly using the final population PK model displaying simulated fluconazole concentrations (left) and proportion of fluconazole troughs of >2,000 ng/ml (right). Min, minimum.