By Michael H. Crawford, MD, Editor
SYNOPSIS: A small patient-applied infuser pump for a pH neutral formulation of furosemide has been developed. A comparison of an intravenous (IV) bolus of furosemide to a five-hour infusion with the pump has been completed and shows that the device is well tolerated and provides similar bioavailability as IV furosemide.
SOURCE: Osmanska J, Brooksband K, Docherty KF, et al. A novel, small volume subcutaneous furosemide formulation delivered by an abdominal patch infuser device in patients with heart failure: Results of two phase I studies. Eur Hear J Cardiovasc Pharm 2023; Oct 6. doi: 10.1093/ehjcvp/pvad073. [Online ahead of print].
In the management of chronic heart failure, intravenous (IV) furosemide is superior to oral furosemide, but IV administration is impractical for outpatients. Subcutaneous (SC) furosemide has been tried but requires large volumes (10 mg/mL), is alkaline, and has low bioavailability. Also, conventional infusion pumps used for SC administration are large and bulky, making them impractical for home use. Thus, a concentrated (30 mg/mL) pH neutral furosemide preparation that can be administered by a small pump specifically designed for this purpose would be attractive. Such a preparation and device has been developed, and two Phase I studies have been completed.
The first study was a pharmacokinetic (PK) and pharmacodynamic (PD) study of the SC furosemide compared to IV furosemide delivered by a large pump in ambulatory patients with heart failure (HF). The second study used the novel small pump administration of furosemide SC in 20 hospitalized patients with HF. In the first study, SC furosemide 80 mg was administered over five hours (30 mg the first hour and 12.5 mg each subsequent hour) using a large conventional pump. This was compared to 80 mg of IV furosemide given over two minutes. This was an open-label, single-dose, randomized, active comparator, crossover, single-center study. After receiving the randomized preparation and after a seven-day washout period, the alternate preparation was given. The primary outcome was relative absolute bioavailability (AB); secondary outcomes were PK and PD.
In the second study, a novel abdominal patch infuser device adapted from the design of an SC insulin pump was used in 20 patients hospitalized with HF. This was an open-label, single-arm, single-center, single-dose study. The primary outcomes included adverse events, device failure, PK, and PD. Study 1 patients were an average age of 71 years, 72% were men, and most were New York Heart Association (NYHA) Class II. The AB of the SC preparation relative to IV furosemide was 112%. Plasma furosemide concentrations were higher with IV administration for the first two hours, but SC concentrations were higher for the last three hours. Median area under the time-concentration curve (AUC) was higher for SC furosemide, as was the half-life (3.70 vs. 3.55 hours). Discomfort during SC administration was reported in five patients (25%), with most in the 0-4 range on a 0-10 pain scale. One patient had level 6 pain and one developed orthostatic hypotension 10 minutes before the end of the infusion. Local skin reactions were observed in four patients (22%).
Study 2 patients’ median age was 75 years and 55% were men. The median left ventricular ejection fraction was 35%, with 12 below 40% and eight above. Injection site discomfort was reported by 12 (60%), of which eight were only at the time of needle insertion. One patient reported pain at level 5. Transient local skin erythema was noted in four patients. No treatment-related adverse events were reported. All 20 patients achieved plasma furosemide levels > 250 ng/mL at 60 and 240 minutes. The authors concluded that administration of furosemide SC via a novel patch pump was feasible, was well tolerated, and had a similar bioavailability to IV furosemide.
COMMENTARY
The ability to deliver IV loop diuretics at home would be a significant advance in HF management. IV is impractical, but SC bolus injections have been tried in selected patients using the standard formulation of furosemide. Skin reactions and pain with this approach have diminished enthusiasm for widespread use.
The development reported in this study of a pH neutral formulation that can be infused SC over several hours by a small patient-applied pump is encouraging. It uses a similar design as the insulin infuser that many patients with diabetes use, which generally is well tolerated. The rate of infusion cannot be changed by the user, which enhances safety. It can be worn under clothes, allowing patient mobility. One hopes that this home use device could decrease hospital readmissions and permit early hospital discharge, resulting in shorter lengths of stay for HF patients.
As expected, the early plasma levels of furosemide provided by the SC pump are lower than those observed with an IV bolus, but the later phase of the infusion provides higher plasma levels, resulting in a bioavailability of 112% over five hours compared to a single bolus. There are limitations to this study. A bolus of furosemide was used as the comparator rather than an infusion. The authors argue that this is the most common way liquid furosemide is used. Also, the pump was applied by the investigators rather than by the patients. However, it is likely that patients will be able to apply this device successfully, as many patients do with the insulin pump.