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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- AUClast
研究概览
简要总结
This study aims to compare the pharmacokinetics and pharmacodynamics of subcutaneous (SC) and intravenous (IV) 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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 45 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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)
研究组 & 干预措施
Treatment Sequence 1
Period 1: SC Period 2: IV
干预措施: SCP-111 (Drug)
Treatment Sequence 1
Period 1: SC Period 2: IV
干预措施: Furosemide USP (Drug)
Treatment Sequence 2
Period 1: IV Period 2: SC
干预措施: SCP-111 (Drug)
Treatment Sequence 2
Period 1: IV Period 2: SC
干预措施: Furosemide USP (Drug)
结局指标
主要结局
AUClast
时间窗: SC SCP-111: 0, 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose. IV Furosemide: 0, 5, 15, 30, 45 minutes and 1, 1.5, 2 hours after 1st IV dose; 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 hours after 2nd IV dose. IV:
Area under the plasma concentration-time curve from time 0 (pre-dose) to time of last measurable plasma concentration.
AUCinf
时间窗: SC SCP-111: 0, 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose. IV Furosemide: 0, 5, 15, 30, 45 minutes and 1, 1.5, 2 hours after 1st IV dose; 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 hours after 2nd IV dose.
Area under the plasma concentration-time curve from time 0 (pre-dose) extrapolated to infinity.
AUCext
时间窗: SC SCP-111: 0, 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose. IV Furosemide: 0, 5, 15, 30, 45 minutes and 1, 1.5, 2 hours after 1st IV dose; 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 hours after 2nd IV dose.
The percentage of the AUC that is extrapolated beyond the last measurable concentration.
Cmax
时间窗: SC SCP-111: 0, 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose. IV Furosemide: 0, 5, 15, 30, 45 minutes and 1, 1.5, 2 hours after 1st IV dose; 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 hours after 2nd IV dose.
Maximum observed plasma concentration of Furosemide
Tmax
时间窗: SC SCP-111: 0, 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose. IV Furosemide: 0, 5, 15, 30, 45 minutes and 1, 1.5, 2 hours after 1st IV dose; 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 hours after 2nd IV dose.
Time of maximum observed Furosemide plasma concentration
λz
时间窗: SC SCP-111: 0, 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose. IV Furosemide: 0, 5, 15, 30, 45 minutes and 1, 1.5, 2 hours after 1st IV dose; 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 hours after 2nd IV dose.
Apparent plasma terminal-phase elimination rate constant
t½
时间窗: SC SCP-111: 0, 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose. IV Furosemide: 0, 5, 15, 30, 45 minutes and 1, 1.5, 2 hours after 1st IV dose; 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 hours after 2nd IV dose.
Terminal-phase half-life
Clearance
时间窗: SC SCP-111: 0, 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose. IV Furosemide: 0, 5, 15, 30, 45 minutes and 1, 1.5, 2 hours after 1st IV dose; 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 hours after 2nd IV dose.
Systemic clearance for IV furosemide (CL) and Apparent systemic clearance for SC furosemide (CL/F)
Volume of Distribution, Terminal Phase
时间窗: SC SCP-111: 0, 5, 15, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose. IV Furosemide: 0, 5, 15, 30, 45 minutes and 1, 1.5, 2 hours after 1st IV dose; 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 hours after 2nd IV dose.
Systemic Volume of distribution, terminal phase for IV furosemide (V) and Apparent Volume of distribution, terminal phase for SC furosemide (Vz/F)
Urine Output 0-6 Hours
时间窗: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6 hours post-dose
Total Urine Output from 0 to 6 hours
Urine Output 0-8 Hours
时间窗: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8 hours post-dose
Total Urine Output from 0 to 8 hours
Urine Output 0-12 Hours
时间窗: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-10, 10-12 hours post-dose
Total Urine Output from 0 to 12 hours
Urinary Sodium 0-6 Hours
时间窗: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6 hours post-dose
Urinary sodium excretion from 0 to 6 hours
Urinary Sodium 0-8 Hours
时间窗: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8 hours post-dose
Urinary sodium excretion from 0 to 8 hours
Urinary Sodium 0-12 Hours
时间窗: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-10, 10-12 hours post-dose
Urinary sodium excretion from 0 to 12 hours
Urinary Potassium 0-6 Hours
时间窗: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6 hours post-dose
Urinary potassium excretion from 0 to 6 hours
Urinary Potassium 0-8 Hours
时间窗: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8 hours post-dose
Urinary potassium excretion from 0 to 8 hours
Urinary Potassium 0-12 Hours
时间窗: 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-10, 10-12 hours post-dose
Urinary potassium excretion from 0 to 12 hours
次要结局
- Injection Site Pain(SC SCP-111: pre-dose, immediately after dose, 15, 30 minutes and 6,12 hours post-dose. IV Furosemide: pre-dose, after place IV needle, immediately after 1st IV dose; 15, 30, minutes, immediately after 2nd dose,15, 30 minutes and 4, 10 hours after 2nd dose)