The proposed study aims to compare the pharmacokinetics and bioavailability of intravenous and subcutaneous Furosemide. Although these regimens are not intended to be bioequivalent, they are both expected to achieve therapeutic plasma levels and induce effective diuresis. The test formulation in this study is a buffered solution, Furosemide Injection Solution at 30 mg/mL at pH 7.4 (range 7.0 to 7.8) and is intended for SC injection according to the instructions in the protocol. A commercial formulation of Furosemide Injection, USP will serve as the reference drug in this study, which will be administered by IV bolus. It contains furosemide 10 mg/mL in solution at alkaline pH of 8.0 to 9.3 and is marketed for IV and IM injection. The primary objective of the study is to estimate the absolute bioavailability of furosemide administered by subcutaneous infusion compared with an equivalent dose of furosemide administered by IV bolus administration.
This study will be an open-label, single-dose, randomized, two-way, two-period crossover study in 20 adult subjects previously diagnosed with mild to moderate heart failure (New York Health Association \[NYHA\] class II/III) being treated with oral furosemide therapy at a dose of ≥40 mg/day. Each subject will complete Screening, Admission, Treatment, and Follow-up Phone Call phases. The Screening Phase will be conducted on an outpatient basis between 28 and 3 days prior to admission. Subjects will be instructed to reduce sodium intake (target \<2 g sodium/day) starting 3 days prior to each of the clinical research unit (CRU) admissions. Admission (Day -1) consists of CRU admission and final qualification assessments. The Treatment Phase will comprise two crossover periods separated by a 7-day outpatient fluid re-equilibration washout. Subjects will discontinue oral furosemide at least 24 hours prior to administration of study drug for each Crossover Period (e.g., no oral furosemide should be administered after 10pm the night prior to CRU admission). Subjects will be randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences (AB or BA) to receive both subcutaneous furosemide (Treatment A; Test) and IV furosemide (Treatment B; Reference) in Crossover Periods (i.e., subcutaneous followed by IV or vice versa). Subjects will remain domiciled in the CRU for each treatment Period during the Treatment Phase through 24 hours after administration of study drug, after which time they will be discharged from the CRU if safety parameters are acceptable to the Investigator. Oral furosemide therapy will be re-initiated at discharge after Treatment 1 (i.e., during the 7-day fluid re-equilibration washout) and after Treatment 2 (i.e., between discharge and Follow-up Phone Call). The Follow-up Phone Call Phase will occur 7 days (± 1) after discharge from the CRU following Treatment 2, completing subjects' study participation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Furosemide Injection Solution for subcutaneous administration (80 mg)
Furosemide Injection, USP (10 mg/mL), 80 mg by intravenous administration
Furosemide Injection Solution for subcutaneous administration (80 mg)
Accel Research Sites - DeLand Clinical Research Unit
DeLand, Florida, United States
AUC Last
Relative absolute bioavailability of furosemide based on AUC last
Time frame: 0 to 24 hours
Cmax
Cmax over 24 hours
Time frame: 0 to 24 hours
Tmax
Tmax over 24 hours. Time to maximum plasma concentration was analyzed using non-parametric rank-based testing. Due to the nature of the statistical analysis, data are presented as Sum Scores rather than traditional descriptive time frames.
Time frame: 0-24 hours
t1/2
half-life
Time frame: 0-24 hours
Urine Volume at 8 Hours
Urine volume collected at 8 hours post dose
Time frame: 0-8 hours
Urine Volume at 24 Hours
Urine volume collected from 8 to 24 hours post dose
Time frame: 8-24 hours
Sodium Concentration in Urine at 8 Hours
Sodium concentration in urine collected from 0 to 8 hours post dose
Time frame: 0 to 8 hours
Sodium Concentration in Urine at 8 to 24 Hours
Sodium concentration in urine collected from 8 to 24 hours post dose
Time frame: 8 to 24 hours
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