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

a b s t r a c t 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.Abbreviations: AE, adverse event; AUC, area under the curve; AUC inf , AUC from time 0 extrapolated to infinity; AUC last , AUC from time 0 to the last quantifiable time point; CI, confidence interval; CL, systemic clearance; CL/F, apparent systemic CL; C max , maximum observed plasma concentration; CV%, coefficient of variation; eGFR, estimated glomerular filtration rate; HF, heart failure; IV, intravenous; NYHA, New York Heart Association; SC, subcutaneous; SD, standard deviation; t 1/2 , terminal elimination half-life; T max , time to T max ; z, terminal phase elimination rate constant; V, systemic volume of distribution; Vz/F, apparent V.