Pharmacokinetics and Pharmacodynamics of a Novel Formulation of Furosemide Administered as a Single Subcutaneous Injection.

Abstract

Purpose: Furoscix (furosemide injection) 80 mg/10 mL is a pH neutral formulation administered subcutaneously (SC) over 5 hours to treat edema in adults with chronic HF or chronic kidney disease. Furosemide 80 mg/mL is a novel concentrated formulation administered as a single 1.0-mL SC injection that could improve convenience for patients. This randomized, open-label, phase 1 study assessed the pharmacokinetics, bioavailability, pharmacodynamics, and safety of furosemide 80 mg/mL SC versus furosemide 80 mg administered intravenously (IV).

Methods: Healthy volunteers were randomized 1:1 to furosemide 80 mg/mL SC or furosemide 80 mg IV (two 40-mg boluses, 2 hours apart), and after a 3-day washout, received the opposite treatment. Plasma furosemide pharmacokinetics, urine output, and urinary sodium and potassium excretion were measured through 12 hours post-dose. Bioavailability (the primary endpoint) was assessed as the least-squares mean ratio (LSMR) of area under the curve (AUC) from time 0-last (AUC_last) and 0-infinity (AUC_inf) between furosemide SC and furosemide IV. Plasma furosemide pharmacokinetics were assessed noncompartmentally. Pharmacodynamics were assessed using a repeated measures, mixed model analysis. Safety was assessed through end of study.

Results: Twenty-one participants were randomized (furosemide SC/IV, n = 10; furosemide IV/SC, n = 11). The furosemide SC/IV LSMR (90% confidence interval [CI]) AUC_last was 106.1% (102.7%, 109.6%), and LSMR (90% CI) AUC_inf was 107.3% (103.9%, 110.8%). Furosemide 80 mg/mL SC had bioavailability equivalent to furosemide 80 mg IV, as the CIs fell within 80.0%-125.0%. Mean (SD) C_max was 4532.9 (1497.7) ng/mL with furosemide 80 mg/mL SC and 10,087.6 (2804.7) ng/mL with furosemide IV. The therapeutic effects of furosemide 80 mg/mL SC on diuresis, natriuresis, and kaliuresis occurred within 1 hour of treatment and were consistent with those of furosemide IV at all time points. There was no significant difference between furosemide 80 mg/mL SC versus furosemide IV in total urine output or urinary sodium or potassium excretion at 0-6 hours, 0-8 hours, or 0-12 hours. Adverse events (AEs) occurred in 14 (66.7%) participants (furosemide SC, n = 11 [52.4%]; furosemide IV, n = 7 [35.0%]) and were mild or moderate. Ten (47.6%) participants had injection site AEs, all of which were treatment-related, mild, non-serious, and resolved. Injection site pain scores graded on a Likert 11-point scale remained low (mean, <0.4; median, 0) at all time points, were similar between groups, and decreased over time.

Conclusions: Furosemide 80 mg/mL SC injection was generally well tolerated and had bioavailability, diuresis, natriuresis, and kaliuresis consistent with those of furosemide IV.