Pharmacokinetics and Pharmacodynamics of Subcutaneous vs Intravenous Furosemide in Healthy Volunteers

Study Overview
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Brief Summary
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This study aims to compare the pharmacokinetics and pharmacodynamics of intravenous (IV) and subcutaneous (SC) furosemide. The test formulation in this study is furosemide injection, 80 mg/1 mL, buffered to a neutral pH for SC administration via an autoinjector. A commercial formulation of furosemide injection, USP, solution 10 mg/mL administered as a 40 mg IV injection over 2 minutes followed by a second dose of 40 mg, 2 hours later, will serve as the reference drug. The objectives of this study are: To estimate the bioavailability and describe the pharmacokinetics and pharmacodynamics of furosemide administered as SC injection via autoinjector compared with equivalent dose of furosemide administered as two 40 mg IV injections, two hours apart. To describe the safety and tolerability of furosemide administered as SC injection via an autoinjector.

Detailed Description
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This is an open-label, single-center, single-dose, randomized, two-way crossover study in healthy volunteers. Each Subject will complete Screening, Baseline, Treatment, and Follow-up Phases. After a Screening Phase, Subjects meeting entry criteria will be admitted to the clinical research unit (CRU) and undergo baseline assessments. Subjects will be randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences (IV furosemide followed by SC or vice versa). Subjects will remain domiciled in the CRU for each treatment period which will be about 12-hours. After final assessments are performed, Subjects may be discharged from the CRU if safety parameters are acceptable to the Investigator and return to the CRU after a 3-day washout period to receive the second treatment sequence. The Follow-up Phase will occur 24-48 hours after discharge from the CRU following treatment sequence 2, completing Subjects' study participation.

Official Title
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Open-label, Single-dose, Randomized, Two-way Crossover Study to Compare the Pharmacokinetics and Pharmacodynamics of Subcutaneous Injection of SCP-111 (Furosemide) vs Intravenous Injection of Furosemide in Healthy Volunteers

Conditions
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Heart Failure, Fluid Overload

Intervention / Treatment
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* Drug: SCP-111
* Drug: Furosemide USP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An Institutional Review Board (IRB) approved informed consent is signed and dated prior to any study-related activities. Male and female subjects 45 to 80 years of age. Has the ability to understand the requirements of the study and is willing to comply with all study procedures. In the opinion of the Investigator, able to participate in the study. Exclusion Criteria: Pregnant or lactating women or women of childbearing age who are not willing to use an adequate form of contraception. Systolic BP (SBP) < 90 mmHg at screening or baseline. Heart rate > 110 beats per minute (BPM) at screening or baseline. Temperature > 38°C (oral or equivalent). Serum potassium < 3.0 or > 5.5 mEq/L at screening. Other significant cardiac abnormalities which may interfere with study participation or study assessments. Current or planned treatment during the study with any IV therapies, including inotropic agents, vasopressors, levosimendan, nesiritide or analogues. scPharmaceuticals, Inc. SCP-111 PK/PD Study Protocol Number: scP-04-001 Confidential Page 14 of 56 Presence of implanted ventricular assist device, cardiac defibrillator or pacemaker. Severely impaired renal function, defined as an estimated glomerular filtration rate (eGFR) at screening admission < 30 mL/min/1.73m2, calculated using the simplified Modification of Diet in Renal Disease (sMDRD) equation. Urinary retention due to bladder emptying disorders and/or urethral narrowing. Presence or need for urinary catheterization. Reported history of hepatic cirrhosis. Administration of intravenous radiographic contrast agent within 72 hours prior to Screening. Concomitant or any use within past 30 days of drugs known to interact with furosemide (aminoglycoside antibiotics, ethacrynic acid, high doses of salicylates, cisplatin, tubocurarine, succinylcholine, chloral hydrate, phenytoin, methotrexate, indomethacin, or lithium). Administration of an investigational drug or implantation of investigational device, or participation in another interventional clinical trial, within 30 days prior to Screening. Any surgical or medical condition which in the opinion of the investigator may interfere with participation in the study or which may affect the outcome of the study. Positive urine drug screen at Screening or Baseline. Blood alcohol concentration > 2 mg/dL (0.02%) at Screening. Alcohol breath test > 2 mg/dL (0.02%) on admission to the CRU. History of severe allergic or hypersensitivity reactions to furosemide or any component of the SCP-111 formulation (tromethamine or benzyl alcohol)

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence 1<br>Period 1: SC Period 2: IV | Drug: SCP-111<br>* Furosemide injection 80 mg/mL, 80 mg SC via autoinjector x 1 dose<br>Drug: Furosemide USP<br>* Furosemide injection, USP 10 mg/mL, 40 mg IV over 2 minutes followed by 40 mg 2 hours later<br>|
| Experimental: Treatment Sequence 2<br>Period 1: IV Period 2: SC | Drug: SCP-111<br>* Furosemide injection 80 mg/mL, 80 mg SC via autoinjector x 1 dose<br>Drug: Furosemide USP<br>* Furosemide injection, USP 10 mg/mL, 40 mg IV over 2 minutes followed by 40 mg 2 hours later<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUClast | The area under the plasma concentration versus time curve from time 0 (pre-dose) to the last quantifiable time point. | 12 hours | 
| AUCinf | The area under the plasma concentration-time curve from time 0 (pre-dose) to time of last measurable plasma concentration. | 12 hours | 
| Cmax | Maximum observed plasma concentration of Furosemide | 12 hours | 
| Tmax | Time to achieve maximum observed Furosemide plasma concentration | 12 hours | 
| λz | Apparent plasma terminal-phase elimination rate constant | 12 hours | 
| t½ | Terminal-phase half life | 12 hours | 
| V | Systemic volume of distribution, terminal phase, for IV furosemide | 12 hours | 
| Vz/F | Apparent volume of distribution, terminal phase, for SC furosemide | 12 hours | 
| CL | Systemic clearance for IV furosemide | 12 hours | 
| CL/F | Apparent systemic clearance for SC furosemide | 12 hours | 
| Urine Output | Total Urine Output | 6 hour, 8 hour and 12 hour | 
| Urinary Sodium | Urinary sodium excretion | 6 hour, 8 hour and 12 hour | 
| Urinary Potassium | Urinary potassium excretion | 6 hour, 8 hour and 12 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 0 through Day 5 visit | 
| Injection Site Pain | Injection site pain will be assessed using an 11-point scale where 0 is equivalent to no pain and 10 is equivalent to the worst possible pain. For IV administration, the 11-point pain scale will be performed. | 12 hours |