Population Pharmacokinetics and Exposure-Safety Analysis of Furosemide in Preterm Infants

Furosemide is the most commonly used diuretic in preterm infants despite an incompletely understood relationship between dosing, exposure, and safety within this population. The goals of this study were to characterize furosemide population pharmacokinetics (popPK) in preterm infants and to evaluate safety by relating simulated furosemide exposure to events of ototoxicity, nephrocalcinosis, and nephrolithiasis. A total of 146 plasma furosemide concentrations from 51 preterm (23-28.9 weeks' gestational age) infants across two studies (one randomized, placebo-controlled, dose-escalating safety trial and one opportunistic, observational study) were included in the analysis. Standard nonlinear mixed effects popPK modeling techniques were applied. Exposure was simulated using the final popPK model (area under the curve) and Monte Carlo simulations (maximum concentration [C_max]). Logistic regression was used to evaluate the relationship between exposure and safety events. The final popPK model was a one-compartment model with the covariates of weight on volume of distribution and both weight and post-natal age on clearance. The model showed accurate predictions, adequate precision, and good model fit. Simulations indicated that furosemide 2 mg/kg administered enterally every 6 h would result in few (approximately 4%) C_max values exceeding a 50 µg/mL threshold reported to be associated with treatment-associated ototoxicity, and no more than 1% for all other dosing regimens. Events of hearing loss, nephrocalcinosis, or nephrolithiasis were rare and showed no relationship with furosemide exposure in logistic regression analysis. These data contributed to the October 2024 FDA label update to include pediatric popPK data and improve dosing in preterm infants.