Most drugs used to treat neonates remain off-label because of the lack of adequately performed PK studies needed to guide dosing. Limitations in blood volume, limited access for obtaining blood samples, reluctance of families to give consent, and potential risks associated with dose-finding studies make performance of PK studies in neonates challenging. Novel approaches are needed to enhance PK knowledge of drugs frequently used in neonates. This protocol, designed with these aforementioned constraints in mind, leveraged routine clinical care as much as possible, and thereby proved both efficient and infant friendly.
We developed a population PK model for fluconazole disposition in preterm and term infants less than 90 days of age who were receiving fluconazole as part of clinically indicated treatment. Population PK analysis allowed the use of limited sampling schemes and the varied dosing regimens used in routine care. Stratified enrollment ensured broad distribution of both BGAs and PNAs. Randomization to two sampling time schedules allowed for more dense sampling times. Because fluconazole is a stable drug, we were able to increase the number of samples available for analysis by scavenging discarded plasma from clinical specimens. Our robust, sensitive quantitative assay allowed us to accurately measure fluconazole in microvolumes of plasma.
In this model, fluconazole CL increased with allometrically scaled weight (1
), BGA, and PNA. PMA, however, did not perform as well as the combination of BGA and PNA. This is not surprising because PMA cannot distinguish a 3-week-old, 24-week-gestation infant from a 1-day-old, 27-week-gestation infant. The model was rigorously evaluated, showed good precision and minimal bias, and was able to estimate into a previously described PK data set in preterm infants (21
Our model suggests that dose adjustment will be needed to account for the significant changes in fluconazole CL that occurs as a function of BGA and PNA. Although pharmacodynamic efficacy exposure targets for infants have not been described, critically ill or immunocompromised adults with invasive candidemia are typically treated with 800 mg/day of fluconazole to target a steady-state AUC of 800 mg · h/liter. This is double the standard dose required to achieve a pharmacodynamic target AUC24
of >50 for Candida
, with the CLSI sensitivity breakpoint MIC being ≤8 (2
). The higher plasma exposure is a reasonable target to ensure adequate tissue exposure in patients with widespread, invasive disease (11
). Plasma concentrations may not always reveal tissue concentration, and tissue concentrations were not available.
For preterm infants with invasive candidiasis, we chose this target AUC of 800 mg · h/liter because these infants have immature immune systems, have a high projected mortality rate, and often have disseminated disease, including meningoencephalitis (7
). A loading dose would be necessary to reach the desired steady-state concentration rapidly. Our data suggest that the lower fluconazole dosages frequently used in the neonatal population result in underexposure and may partially explain the prolonged periods of candidemia (5
) and episodes of breakthrough candidemia (23
Although the neonatologists caring for these infants reported no adverse events, and none of the infants developed a breakthrough fungal infection, a limitation of this study is that comprehensive efficacy and safety data (e.g., liver function tests results, electrocardiograms, etc.) were not collected and thus could not be linked to exposure. Furthermore, we were unable to evaluate drug-drug interactions.
Longitudinal prediction of CL changes with PNA beyond 14 days is difficult. Infants who enrolled when they were more than 14 days old were often receiving fluconazole during periods of clinical deterioration secondary to sepsis or necrotizing enterocolitis. This model may underpredict CL beyond 14 days of age in infants who are relatively well and receiving fluconazole prophylaxis from birth. We plan to perform sparse PK sampling in infants who will be enrolled into a multicenter trial of fluconazole prophylaxis to improve our longitudinal prediction of changes in CL with PNA in these relatively well infants.
Pharmacokinetic neonatal study designs that leverage routine clinical care can provide reliable PK information. The fluconazole population PK model from this nontraditional design was able to accurately predict the observed fluconazole concentrations in a historic, more traditional PK study. Incorporating both BGA and PNA improved the model fit beyond that achieved with PMA. BGA and PNA effects on CL are significant, and dose adjustments will likely be needed. Our future studies will use Monte Carlo simulation to fully explore dose-exposure relationships, evaluate the effects of a loading dose, and guide further development of pharmacologically rational neonatal dosing recommendations.