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.

External Evaluation of Two Fluconazole Infant Population Pharmacokinetic Models

“…Patient-level data from two separate studies were used for the analyses described herein. The study designs of these two studies have been previously described in detail, and, again, these are referred to as the "PPRU study" (9) and the "prophylaxis study" (5).…”

“…Available as an injection, tablet, and oral (p.o.) suspension, fluconazole is well absorbed, with its oral bioavailability (F) estimated to be Ͼ90% (4,5). Following oral administration, fluconazole reaches its maximum concentration (C max ) in approximately 1 to 2 h (4).…”

“…This study is henceforth referred to as the "PPRU study." The second study characterized the disposition of fluconazole using data collected through a multicenter, randomized, placebo-controlled trial evaluating the efficacy and safety of fluconazole prophylaxis in infants weighing Ͻ750 g at birth (5). This study is henceforth referred to as the "prophylaxis study."…”

“…This study is henceforth referred to as the "prophylaxis study." Both the PPRU and prophylaxis studies used a one-compartment PK model to describe the fluconazole concentration data, and both identified patient age and the serum creatinine concentration (SCR) to be important covariates explaining the interindividual variability (IIV) in the clearance (CL) of fluconazole (5,9).…”

Pharmacometric Modeling and Simulation Is Essential to Pediatric Clinical Pharmacology

“…38 Another problem with scavenged samples occurs if the analyte degrades rapidly at room temperature, such as for penicillins, and model estimates of parameter values may be biased if based on scavenged samples that are not absolutely fresh or frozen when fresh. 39 Nevertheless, scavenged sampling strategies have been used for numerous drugs in neonatal populations, including ampicillin, 40 clindamycin, 41 fluconazole, 42,43 metronidazole, 44 and piperacillin. 45 From an optimal sampling perspective, D-optimal is the most commonly used criterion, as previously mentioned.…”