Abstract Body (Do not enter title and authors here): Background: Decongestion is the primary treatment for most episodes of acutely decompensated heart failure (ADHF). However, in patients presenting with volume overload, outpatient decongestion can be challenging due to the reduced bioavailability of oral diuretics; thus, necessitating hospitalization for intravenous (IV) diuretics. Persistent congestion at hospital discharge is common and associated with high readmission rates and poor patient outcomes. Bumetanide Nasal Spray (BNS) is a novel intranasal diuretic formulation that has the potential to overcome oral diuretic resistance associated with congestion-related gastrointestinal impairment and may offer an effective outpatient self-administered parenteral diuretic option for stable congested patients not responding to oral (PO) diuretics.

Methods: To assess the comparative safety and efficacy of bumetanide, 68 healthy adults were randomized to receive BNS, PO, and IV bumetanide in a fully replicated design. Safety was assessed through daily physical exams and by monitoring serum and urine electrolyte concentrations. Efficacy was evaluated by comparing pharmacokinetics (PK) and pharmacodynamics (PD) in blood and urine at prespecified time intervals. Urine sodium (Na), potassium (K), albumin (Alb), and creatinine (Cr) excretion were also measured. An ANCOVA model was used to compare the pharmacodynamics between treatments.

Results: Bioequivalence between 2 mg BNS and 2 mg PO was established for Cmax, AUC0-t, and AUC0-inf. BNS demonstrated a 33% faster Tmax vs PO (1.0 vs. 1.5 hours, respectively). As expected, the PK comparison of BNS and PO to IV showed lower Cmax values. Diuresis was equivalent for all three routes, beginning 2 hours after administration. Na and K excretion were similar between BNS and PO and higher than with IV treatment. BNS also showed an earlier onset of natriuresis compared to IV.

BNS was well tolerated, with fewer treatment-emergent adverse events (TEAEs) reported for BNS compared to PO (16.2% vs. 23.9% of subjects, respectively).

Conclusions: Among a diverse group of healthy adults, BNS was well tolerated, safe, and had equivalent efficacy vs. IV and PO administration. BNS may be a useful new self-administered outpatient option for congested patients who demonstrate oral diuretic resistance due to impaired gastrointestinal absorption or motility. BNS may also have utility for congested dysphagic patients. Studies evaluating BNS in congested patients are forthcoming.