Population pharmacokinetics of fluconazole in young infants

Abstract

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 . (weight/1)(0.75) . (BGA/26)(1.739) . (PNA/2)(0.237) . serum creatinine (SCRT)(-4.896) (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 . (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

FIG. 1.

Scatter plot of variance term for CL (ETA1) using the base model. Correlation between variances on CL (ETA1) and the following variables: variance on V (ETA2) (A), BGA (B), PNA (C), and PMA (D).

FIG. 2.

Final model diagnostic plots of observed versus predicted fluconazole concentration and weighted residuals. For population prediction (A) and individual prediction (B), the individual data points are labeled by individual ID numbers with a dotted line connecting individual data points. Line of identity is included as a reference. For weighted residuals (C), individual data points are labeled by individual ID numbers with a dotted line as a smoothing spline trend line through the data. A solid line at y = 0 is included as a reference.

FIG. 3.

Predictive check for plasma fluconazole concentration by day of life. Observed fluconazole concentrations (open circles) in a previously published Saxén trial (21) of twelve 26- to 29-week-gestation infants receiving 6 mg/kg fluconazole on day of life 0 (birthday), 3, 6, 9, and 12 are superimposed with the median (dotted line) and 90% population prediction interval (shaded area) for fluconazole concentrations from 100 Monte Carlo simulated trials, given the final model and parameters. Bold arrows indicate fluconazole doses that preceded plasma PK samples. Open lines indicate fluconazole doses that were not followed by plasma PK samples.

FIG. 4.

Evaluation of dose exposure relationship. The median (dark line) and population predicted interval from the 10th percentile to the 90th percentile (shaded area) for fluconazole AUC from 100 Monte Carlo simulated trials, given the final model and parameters. Simulated 24-h interval AUC for each day of therapy among 23- to 29-week-gestation infants (A) or 30- to 40-week-gestation infants (B) receiving 12 mg/kg/day fluconazole. (C) Median box plot of predicted dose required to achieve steady-state AUC target of 800 mg · h/liter in infants stratified by BGA and PNA.