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

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.