An Adult Population Pharmacokinetic Model to Simulate Subcutaneous Administration of a Fixed Dose of Furosemide in Adolescents with Heart Failure and Volume Overload

Abstract

Background: Subcutaneous furosemide administered with the On-Body Infusor could be useful in children with heart failure (HF) and congestion due to volume overload, but the appropriate dosing regimen is unknown.

Objective: This study aimed to develop a population pharmacokinetic (popPK) model to determine the subcutaneous furosemide dosing regimen in children with HF who are appropriate for On-Body Infusor use.

Methods: Samples collected from 15 adults with HF who received subcutaneous or intravenous furosemide in a randomized phase II/III study (NCT02329834) were used to develop the popPK model with covariates identified by forward inclusion and backward elimination; validation was by bootstrapping. The model was allometrically scaled from a 70-kg adult body weight to simulate furosemide pharmacokinetics in virtual adolescents aged 12-17 years by weight category (42.5-50.0, > 50-60, and > 60-70 kg) for subcutaneous furosemide 80 mg (30 mg over 1 h then 12.5 mg/h for 4 h).

Results: Furosemide pharmacokinetics were best characterized using a two-compartment model with first-order absorption and elimination. After scaling to adolescents in subcutaneous dosing simulations, estimated furosemide clearance was 1.55 mL/min/kg. Estimated exposure (mean area under the plasma concentration-time curve at 24 h) was 16,800 µg⋅h/L in adolescents weighing 42.5-50.0 kg, 14,700 µg⋅h/L in adolescents weighing > 50-60 kg, and 13,000 µg⋅h/L in adolescents weighing > 60-70 kg versus 12,400 µg⋅h/L in adults.

Conclusions: Simulated furosemide exposure was consistent with published values, supporting an 80-mg dose of subcutaneous furosemide (30 mg over the first hour, then 12.5 mg/h for 4 h) for adolescents aged 12-17 years with body weight ≥ 42.5 kg.

Fig. 1

Visual predictive check of furosemide observation versus time after dose stratified by administration route. a Intravenous furosemide administration. b Subcutaneous furosemide administration. Open circles represent individual observations (n = 15) of furosemide concentrations. Red dashed lines represent the observed data 5th percentile (bottom line), 50th percentile (middle line) and 95th percentile (top line). Grey solid lines indicate the simulated data (n = 1000) 5th percentile (bottom line), 50th percentile (middle line), and 95th percentile (top line). Grey shaded areas represent the 90% confidence interval.

Fig. 2

Simulated furosemide concentration versus time profiles simulated in adolescents versus adults. Using the final pharmacokinetic model, furosemide concentration versus time profiles were simulated for a fixed 80-mg dose of furosemide for adolescents aged 12–17 years with body weights of a 42.5–50 kg, b > 50–60 kg, and c > 60–70 kg versus a typical 70-kg adult. The 50th percentiles are represented by dashed lines for adults and solid lines for adolescents. The 5th and 95th percentiles of simulated concentration are represented by grey areas (adults) and colored areas (adolescents; red, 42.5–50 kg; blue, > 50–60 kg; green, > 60–70 kg).