391 - Furosemide pharmacokinetics in infants with established bronchopulmonary dysplasia using whole blood microsampling

Publication Number: 3378.391

Nicolas A. Bamat, Children's Hospital of Philadelphia, Swarthmore, PA, United States; Heidi Morris, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Matthew M. Laughon, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Jonathan M. Davis, Tufts University School of Medicine, Boston, MA, United States; Manjunath Pai, University of Michigan Pharmacokinetics Core Laboratory, Ann Arbor, MI, United States; James L. Bruton, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Scott A. Lorch, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States; Kevin J. Downes, Children's Hospital of Philadelphia, Philadelphia, PA, United States

Background: Furosemide is the most frequently prescribed pharmacotherapy in very preterm (VP) infants with established bronchopulmonary dysplasia (BPD). Based on pharmacokinetic (PK) studies in preterm infants at 31-32 weeks (w) postmenstrual age (PMA) estimating low (7-11 ml/h/kg) clearance (CL), the FDA recommends the maximum dose for preterm infants "not exceed 1 mg/kg/day" to avoid potential toxicities. While prior research suggests CL may increase with maturation, furosemide PK in infants with BPD beyond 36w PMA is unknown.

Objective: To characterize and identify factors that influence furosemide PK in infants with BPD beyond 36w PMA.

Design/Methods: We conducted a prospective observational PK study with informed consent in VP infants with grade 2 or 3 BPD prescribed furosemide for clinical indications while hospitalized between 36-60w PMA. We obtained 5 whole blood volumetric absorptive microsamples (VAMS, 10 uL) via heelstick at pre-specified time windows around intravaneous (IV) or enteral (gastric or duodenal) furosemide administrations. Subjects could provide repeated sets of 5 samples if administration route changed or if they aged at least 6w from an early (36-47w) to a late (48-59w) PMA range. Furosemide was quantified with a validated and published VAMS assay. We developed a parametric population PK model with Monolix, applying allometric scaling for weight. Covariate selection took place in a stepwise fashion based on improvement in Bayesian information criterion and objective function values.

Results: We analyzed 265 VAMS samples from 34 infants around 53 furosemide doses at a median PMA of 48w (Table 1). A two-compartment model with allometric scaling normalized to the median population weight (4.7 kg) best described the data. PMA (described as a Hill function) and estimated glomerular filtration rate (eGFR) were significant covariates on CL. Model diagnostic plots showed adequate model performance (Fig. 1). Table 2 displays final PK parameter estimates. The typical value of CL in our population was 423 (95% CI: 338-530) ml/h/kg^0.75.

Conclusion(s): Furosemide CL is markedly higher in older infants with established BPD compared to earlier estimates at 31-32w PMA, likely reflecting the maturation of organic anion transporters secreting furosemide into the renal tubules. Increasing PMA and greater eGFR may be considered in individualized dose adjustments. Although our data suggest the risk of toxicity is lower in older infants with established BPD compared to younger preterm infants, alternate dosing strategies and furosemide safety and efficacy in infants with established BPD requires dedicated study.

Table 1. Study population and pharmacokinetic sampling occasion characteristics


Table 2. Final population PK parameter estimates for furosemide in infants with established bronchopulmonary dysplasia


Figure 1. Model diagnostic plots for population pharmacokinetics of furosemide in infants with established bronchopulmonary dysplasia
A. Observed vs population predicted concentrations. B. Observed vs individual predicted concentrations. C. Visual predictive check of observed concentrations vs time after dose. Blue dots represent measurable observed concentrations. Red dots represent concentrations below the limit of quantification (0.05 mg/L).