Bumetanide nasal spray: a novel approach to enhancing diuretic response and advancing ambulatory heart failure care?

Abstract

Loop diuretics are the cornerstone of managing congestion in heart failure (HF). It is hypothesized that in heavily congested patients, gut edema may lead to lower bioavailability of oral drugs, including diuretics, which, in turn, may lead to insufficient diuresis. Intravenous (IV) loop diuretics are often required to achieve rapid diuresis due to their high plasma concentrations. However, reliance on IV administration limits options in ambulatory settings, where effective rescue therapies are needed. Bumetanide Nasal Spray (BNS) is a novel formulation designed to overcome absorption challenges and provide rapid, high bioavailability through intranasal administration. This mini-review summarizes the results of the recently presented bioavailability study of BNS conducted in healthy individuals, showing its bioequivalence to oral formulations. Lastly, the paper discusses the potential caveats and limitations of the trial and further perspectives.

Background

Loop diuretics are the first-line treatment for congestion and are used to control a patient’s volume status in heart failure (HF). The inability to maintain volume homeostasis results in decompensation and the need to seek medical help, which results in hospital admission and/or escalation of diuretic therapy. Most patients admitted to the hospital receive intravenous (IV) loop diuretics, regardless of their perfusion status or other factors, including geographical location [1]. The idea behind the IV route of drug administration is related to the fact that high plasma concentrations of the loop diuretic are needed to cross a threshold level above which rapid and effective diuresis is achieved [2]. Although the pathophysiology of acute decompensated HF is very complex and not completely understood, one element that may add to this cascade of events is decreased diuretic responsiveness [3]. It has been demonstrated that the chronic use of loop diuretics leads to blunted diuretic response in acute decompensated HF and that this is related to functional and structural tubular remodeling, which are the major known determinants of diuretic response, together with neurohormonal drive and hemodynamic disturbances [4, 5]. Moreover, it was hypothesized that patients experiencing congestion may also have gut edema, which could decrease the bioavailability of oral drugs such as loop diuretics [6, 7]. This, in turn, might further exacerbate the spiral of congestion and impair diuretic response. This effect compels physicians to increase the oral chronic dose. Currently, for ambulatory use, only oral and (in some countries) subcutaneous furosemide are available [8]. Still, these are not optimal for ambulatory rescue therapy when a high plasma concentration of the drug is needed in a relatively short time. So, formulations that could bypass the potential absorption block and provide high bioavailability might turn out to be both effective (in terms of diuresis) and beneficial (in terms of congestion reduction and improvement of ambulatory care).

Bumetanide Nasal Spray (BNS)

One of the potential solutions to overcome gastrointestinal absorption issues that could lead to rapid and high bioavailability is the nasal administration of the drug formulation with high mucosal absorption. Bumetanide Nasal Spray (BNS) is a new intranasal loop diuretic designed for absorption through the nose application. During the recent AHA meeting in Chicago in 2024, the results of a randomized pharmacokinetic/pharmacodynamic open-label, crossover study of BNS were presented and simultaneously published [9]. The study’s primary outcomes were a comparison of (1) C_max (maximum concentration) and (2) AUC (area under the curve) for BNS vs. oral bumetanide vs. IV bumetanide. The secondary endpoints included safety measures (like impact on ECG, basic vitals, laboratory tests, etc.), comparison of AUC (Area Under the Curve), T_max (Time to Maximum Concentration), T_1/2 (Biological Half-life), V_dis (Volume of Distribution), plasma clearance, and absolute bioavailability between nasal vs. IV administrations, as well as pharmacodynamic endpoints including urine output and Na⁺ excretions.

The study recruited healthy individuals (n = 68, mean age 39 ± 9 years, BMI 26.2 ± 3.2 kg/m²) who were housed in the research facility for 10 days and examined after exposure to different Bumetanide formulations (BNS 2 mg, oral 2 mg, and IV 2 mg). There was a 48-h washout period after each randomly assigned exposure, during which participants’ volume status could recover.

The study met its primary endpoint: BNS was bioequivalent to oral bumetanide for key pre-defined parameters. There was no difference in C_max (Maximum Plasma Concentration) between BNS and oral bumetanide, nor was there any difference in AUC. BNS had shorter T_max than tablets (1 h vs. 1.5 h), indicating that peak plasma drug concentrations were detected slightly earlier after the nasal application. Importantly, there was no difference between all examined formulations in urine output in 2 h and 24 h. The mean urine volumes in the time points were approximately 2 L and 6 L, respectively. Similarly, cumulative sodium excretion was the same regardless of the route of administration (i.e., intranasal, intravenous, or oral), reaching approximately 140 mmol at 2 h and ~ 300 mmol during 24 h. The presented safety profile of all formulations was comparable. There was only one case of nasal dryness reported after nasal application.

What new do we learn from the study?

The study has demonstrated a very good bioavailability of BNS, equivalent to oral and IV applications in healthy individuals. BNS may have potential advantages; it could be used as a rescue therapy in ambulatory settings since it does not need medical personnel for administration (i.e., IV loop diuretics) or proctored teaching (i.e., subcutaneous). Compared to the available subcutaneous solutions, the intranasal formulation is non-invasive, does not require a device to be continuously attached to the body, and can be self-administered on demand, providing greater convenience and ease of use for patients in ambulatory settings (see Table 1). However, no direct pharmacokinetic comparisons are available. BNS also avoids the first-pass metabolism that may be important in chronic diuretic users, as bumetanide is metabolized in the liver. However, this effect could not be seen in healthy individuals. As the intranasal form bypasses the potential gastrointestinal absorption block in heavily congested patients, it might have better bioavailability in those patients vs. tablets. However, those statements need to be tested in well-designed prospective studies. There is data, though, that chronic HF patients have considerably prolonged absorption compared to healthy individuals, leading to lower peak concentrations of diuretics [10].

Table 1.

Comparison of different formulations of bumetanide

	Nasal spray administration (1–2 mg)	Oral administration (1–2 mg)	Intravenous administration (1–2 mg)	Intramuscular administration (1–2 mg)
Bioavailability	Decreased by nasal congestion (0.62 ± 0.3)	Decreased by food (0.62 ± 0.24)	0.66 ± 0.112	0.70 ± 0.10
Half-life	1–1.5 h	1.5–2 h	3.1 h	47–139 min
Practical use	On demand (1–2 times/day)	2–3 times/day	2 times/day	1–2 times/day
Plasma clearance	unknown	228–255 ml/min	228 ml/min	320–400 ml/min
Peak plasma	20–30 min	30 min	30 min	38 min
Protein binding	85%	90%	93%	90%
Limitations	• The serum concentration may rely on proper application • The application technique may be important • Nasal mucosal congestion and other mucosal issues may limit efficacy • Not high-quality data (RCT) are available to support its use	• The tolerance to the treatment develops; (however, this is not limited to the oral formulation only)	• Intravenous access is needed • Rather limited to in-hospital use, in many countries	• Subcutaneous access needs to be maintained • The risk of local complications
Advantages	• Easy for ambulatory use • might be used as a rescue dose, • easy of application, • Bypasses the first pass effect	• A well-known, • well-implemented, • inexpensive, • widely accepted method	• Effective • A well-known, • well-implemented, • inexpensive, • widely accepted method	• The patient does not need to remember to take a pill • High adherence to the therapy

However, there are some important caveats to the concept. Although a nasal diuretic may help bypass one potential (and so far weakly scientifically supported) aspect of diuretic resistance (absorption blockade), we need to emphasize that in most patients, diuretic resistance results from blockade at the kidney level [4, 11]. This issue cannot be overcome by merely changing the route of administration, and additional strategies are required (i.e., sequential nephron blockade with a thiazide-type diuretic). This brings the possibility that other types of diuretics (or even their “one-shot” combinations) and other HF therapies might also be administrated through nasal applications.

Second, more data is needed to ensure that the nasal spray is really predominantly absorbed in the nasal cavity. With larger volumes of nasal spray, at least some part of the spraying solution will be swallowed, meaning all potential advantages mentioned above will not apply. Thus, the exact proportion of the dose absorbed nasally vs. orally, as well as the impact of variability in administration technique on overall bioavailability, remains to be further investigated. We also need to remember that the study was conducted on healthy volunteers, which limits the generalizability of the results. Thus, the results may not fully reflect the pharmacokinetics in HF patients with chronic kidney disease, sodium avidity, and altered drug metabolism. Moreover, the potential barriers to intranasal absorption (and its unpredictability bioavailability) include nasal congestion, congestion-related nasal secretions, mucosal inflammation, and variability in spray technique, which may be particularly relevant in HF patients that usually have many co-morbidities, including sleep-disordered breathing. Moreover, the paradigm of the diuretic-centric approach should be changed as the disease-modifying groups of drugs should also be emphasized as therapies meant to decrease the risk of decompensation and even improve natriuresis [12, 13].

To conclude, the results presented are promising and highlight the need for the further development of new formulations and diuretic approaches in HF. BNS provides an innovative, non-oral method for administering loop diuretic therapy that could be used in outpatient settings. The real advantages and limitations of using BNS in congested HF patients are still to be identified, as it is not clear at this point and cannot be concluded from the presented study. Future prospective, adequately powered, randomized studies in HF populations should be conducted to evaluate whether the intranasal application of bumetanide will benefit HF patients.

Author contributions

J.B. wrote the first draft of the manuscript text. All authors reviewed and corrected the manuscript. All authors contributed to the manuscript.

Funding

Wroclaw Medical University, SUBZ.A460.24.040.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.