Abstract 4351158: Pharmacodynamics (PD) of a Subcutaneous (SC) Injection of a Novel-Formulation of furosemide (FUR)

Introduction: Furoscix 80 mg/10 mL is a buffered formulation of FUR that is self-administered SC via an On-body Infusor over 5 hrs. SCP-111 (FUR SC) is a novel-formulation of FUR 80 mg/mL currently in development that is administered as a single dose via SC injection. FUR SC demonstrated 107.3% relative bioavailability to furosemide IV; [90% CI 103.9, 110.8] with similar urine output (UO) at 6, 8 and 12 hours. Research Questions/Goal: Explore pharmacokinetics (PK) and PD of FUR SC, notably hourly UO and Na excretion, and relationship between furosemide plasma concentration and effect. Methods: Post-hoc analysis from randomized, open-label, single-center crossover study. Healthy participants were randomized 1:1 to 1 of 2 treatment sequences (FUR IV 80 mg [two IV 40-mg boluses 2 hours apart] or FUR SC 80 mg/mL via autoinjector into abdomen). Opposite treatment was administered after 3-day washout. Blood was collected pre-dose and for 12 hours post-dose to determine FUR plasma concentrations. Urine was collected for 12 hours post-dose to determine urine output (UO) and urinary Na excretion. Mean hourly UO and Na excretion from FUR SC and FUR IV were plotted against time (hours) across the 12-hour study period. Mean hourly UO and Na excretion were subsequently plotted against FUR concentrations from SC and IV, and best-fit curves were generated to determine respective UO and Na excretion thresholds. Results: 21 subjects were randomized and 19 had sufficient sample estimation of PK and PD parameters. Mean (SD) UO and Na excretion peaked at 1 hour for both FUR SC [1026.1 (295.5) mL and 101.4 (30.8 mmol)] and FUR IV [1011.6 (346.1) mL and 104.3 (39.0) mmol] and was consistent between routes over the 12-hour duration (Figure 1). A sigmoidal concentration-response curve was observed for both mean hourly UO and Na excretion, which is consistent with the established general pharmacology of loop diuretics. Conclusions: FUR SC demonstrated similar hourly diuresis and natriuresis over the 12-hour period compared to FUR IV. Plasma furosemide concentrations from both SC and IV administration correlated with UO and Na excretion, which is consistent to that reported in the literature. Furosemide 80 mg/mL administered as a SC injection is a potential alternative to IV administration, with similar PK and PD.