Investigation of Pharmacokinetics, Safety, and Tolerability of BAY 94-8862 in Male and Female Subjects With Renal Impairment and in Age- and Weight-matched Healthy Subjects Following a Single Oral Dose of 10 mg BAY 94-8862 IR Tablet in a Single-center, Non-randomized, Non-controlled, Non-blinded, Observational Study With Group Stratification
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Bayer
- 入组人数
- 33
- 主要终点
- Area under the plasma concentration vs time curve from zero to infinity for total (bound and unbound) drug after single dose administration of BAY94-8862 (AUC)
研究概览
简要总结
Researchers are looking for a better way to treat people who have worsening of chronic heart failure, a long-term condition where the heart does not pump blood as well as it should.
In this study researchers wanted to learn more about a new substance called finerenone (BAY94-8862).
Finerenone is a substance that blocks the activation of a protein in the body called mineralocorticoid receptor (MR). An increased activation of MR is involved in the development of hypertension, organ damage and worsening of heart failure. Many patients with worsening chronic heart failure also suffer from chronic kidney disease. Chronic kidney disease is a long-term decrease in the kidneys' ability to work properly.
The researchers studied how finerenone moves into, through and out of the body. The researchers also looked at how safe finerenone is and how it affects the body. The main purpose of this study was to help researchers develop recommendations for the amount of the substance (the dosing) to be given to patients with reduced kidney function.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •The informed consent must be signed before any study specific tests or procedures are done;
- •Male participants and female participants without childbearing potential (postmenopausal women with 12 month of spontaneous amenorrhea or with 6 month of spontaneous amenorrhea and serum follicle-stimulating hormone (FSH) levels >30 mIU/mL; women with 6 weeks post bilateral ovarectomy, women with bilateral tubal ligation, and women with hysterectomy);
- •Age: 18 to 79 years at the first screening examination;
- •Race: White;
- •Body mass index (BMI): ≥ 18 and ≤ 34 kg / m2;
- •Participants with renal impairment
- •Creatinine clearance (CLCR) ≤ 80 mL/min determined from a 24 hour urine collection interval 2 - 14 days prior to dosing;
- •Stable renal disease, ie a serum creatinine value determined at least 3-6 months before the pre-study visit should not vary by more than 20% from the serum creatinine value determined at the pre-study visit;
- •Healthy participants
- •Mean age and body weight in Group 1 (control group, healthy participants) and Groups 2 - 4 should not vary by more than +/- 10 years and +/- 10 kg, respectively.
排除标准
- •Participation in another clinical trial during the preceding 3 months for multiple dose studies and 1 month for single-dose studies; (final examination from previous study to first treatment of new study);
- •Exclusion periods from other studies or simultaneous participation in other clinical studies;
- •Donation of more than 100 mL of blood within 4 weeks before the first study drug administration or more than 500 mL in the preceding 3 months;
- •Regular use of following medication during or within the 1 - 2 weeks preceding the study:
- •concomitant administration of other Aldosterone-antagonists (eg. eplerenone or spironolactone), potassium-sparing diuretics, potassium supplements, nonsteroidal anti-inflammatory drugs like ASS (secondary prevention with a dose of 100 mg daily is allowed), indomethacin or ibuprofen
- •concomitant use of cytochrome P450 isoenzyme 3A4 (CYP3A4) inducers (eg St. John´s wort, rifampicin, carbamazepin, phenytoin, phenobarbital, bosentan)
- •concomitant use of weak to moderate CYP3A4 inhibitors (eg erythromycin, quinupristin/dalfopristin, saquinavir, fluconazole, amiodarone, diltiazem, fluvoxamine, verapamil, valproic acid, fluoxetine, grapefruit juice)
- •strong inhibitors of CYP3A4 (eg human immunodeficiency virus (HIV) protease inhibitors like indinavir, nelfinavir, ritonavir, atazanavir, lopinavir, amprenavir and saquinavir; macrolide/ketolide antibiotics like clarithromycin, telithromycin; antimycotic agents like itraconazole and ketoconazole [topical formulations will be allowed]; nefazodone)
- •moderate and strong inhibitors of cytochrome P450 isoenzyme 2C8 (CYP2C8) (eg gemfibrozil, montelukast, trimethoprim, glitazones)
- •Women of childbearing potential, pregnant or lactating women;
- •Positive results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV), human immune deficiency virus antibodies (anti-HIV 1+2);
- •Serum potassium level ≥ 5.5 mmol/L;
- •Serum sodium level ≤ 130 mmol/L;
- •For participants with renal impairment
- •Acute renal failure;
- •Acute nephritis;
- •Any organ transplant;
- •Failure of any other major organ system other than the kidney;
- •Diastolic blood pressure (DBP) > 100 mmHg and/or systolic blood pressure (SBP) > 180 mmHg (at the pre-study examination; readings taken at the end of the dosing interval of antihypertensive medication, if any);
- •Heart rate below 45 or above 110 BPM at screening visit;
- •Hemoglobin < 8 g/dL;
- •Serum albumin < 30 g/L;
- •Severe cerebrovascular or cardiac disorders, eg myocardial infarction less than 6 months prior to dosing, congestive heart failure of New York Heart Association (NYHA) grade III or IV, decompensated heart failure, severe arrhythmia requiring antiarrhythmic treatment;
- •For healthy participants
- •A history of relevant diseases of vital organs, of the central nervous system or other organs;
- •Systolic blood pressure below 100 mmHg or above 145 mmHg;
- •Diastolic blood pressure above 95 mmHg;
- •Heart rate below 45 or above 95 BPM at screening visit;
- •Clinically relevant deviations of the screened laboratory parameters in clinical chemistry, hematology, or urinalysis from reference range;
- •Relevant deviation from the normal range in the clinical examination as judged by the investigator.
研究组 & 干预措施
Normal renal function
Healthy participants with creatinine clearance (CLCR) >80 mL/min received single oral dose of 10 mg BAY94-8862 as an IR tablet under fasting conditions.
干预措施: Finerenone (BAY94-8862) (Drug)
Mild renal impairment
Participants with CLCR 50-80 mL/min received single oral dose of 10 mg BAY94-8862 as an IR tablet under fasting conditions.
干预措施: Finerenone (BAY94-8862) (Drug)
Moderate renal impairment
Participants with CLCR 30-<50 mL/min received single oral dose of 10 mg BAY94-8862 as an IR tablet under fasting conditions.
干预措施: Finerenone (BAY94-8862) (Drug)
Severe renal impairment
Participants with CLCR <30 mL/min received single oral dose of 10 mg BAY94-8862 as an IR tablet under fasting conditions.
干预措施: Finerenone (BAY94-8862) (Drug)
结局指标
主要结局
Area under the plasma concentration vs time curve from zero to infinity for total (bound and unbound) drug after single dose administration of BAY94-8862 (AUC)
时间窗: Up to 96 hours post-dose
AUC for BAY94-8862 and its metabolites M1 (BAY1040818), M2 (BAY1088089) and M3 (BAY1088090)
Cmax for unbound drug (Cmax,u)
时间窗: Up to 96 hours post-dose
Cmax,u BAY94-8862 and its metabolites M1 (BAY1040818), M2 (BAY1088089) and M3 (BAY1088090)
Cmax divided by dose per body weight (Cmax,norm)
时间窗: Up to 96 hours post-dose
Cmax, norm for BAY94-8862 and its metabolites M1 (BAY1040818), M2 (BAY1088089) and M3 (BAY1088090)
Maximum total (bound and unbound) drug concentration in plasma after single dose administration of BAY94-8862 (Cmax)
时间窗: Up to 96 hours post-dose
Cmax for BAY94-8862 and its metabolites M1 (BAY1040818), M2 (BAY1088089) and M3 (BAY1088090)
AUC for unbound drug (AUCu)
时间窗: Up to 96 hours post-dose
AUCu for BAY94-8862 and its metabolites M1 (BAY1040818), M2 (BAY1088089) and M3 (BAY1088090)
AUC divided by dose per kg body weight (AUCnorm)
时间窗: Up to 96 hours post-dose
AUCnorm for BAY94-8862 and its metabolites M1 (BAY1040818), M2 (BAY1088089) and M3 (BAY1088090)
Cmax,norm for unbound drug (Cmax,u,norm)
时间窗: Up to 96 hours post-dose
Cmax,u,norm for BAY94-8862 and its metabolites M1 (BAY1040818), M2 (BAY1088089) and M3 (BAY1088090)
AUCnorm for unbound drug (AUCu,norm)
时间窗: Up to 96 hours post-dose
AUCu, norm for BAY94-8862 and its metabolites M1 (BAY1040818), M2 (BAY1088089) and M3 (BAY1088090)
次要结局
- Plasma angiotensin II(Prior to dosing and 12 hours post-dose)
- Serum aldosterone(Prior to dosing and 12 hours post-dose)
- Plasminogen activator inhibitor-1 (PAI-1)(Prior to dosing and 12 hours post-dose)
- Urinary electrolytes(Prior to dosing up to 24 hours post-dose)
- Half-life associated with the terminal slope (t½)(Up to 96 hours post-dose)
- Plasma renin activity (PRA)(Prior to dosing and 12 hours post-dose)
- Urinary volume(Prior to dosing up to 24 hours post-dose)
- Urinary creatinine(Prior to dosing up to 24 hours post-dose)
- AUC divided by dose (AUC/D)(Up to 96 hours post-dose)
- Cmax divided by dose (Cmax/D)(Up to 96 hours post-dose)
- Total body clearance of drug calculated after extravascular administration (CL/F)(Up to 96 hours post-dose)
- Fraction unbound (fu)(1 hour and 6 hours post-dose)
- Apparent volume of distribution during terminal phase after extravascular administration (Vz/F)(Up to 96 hours post-dose)
- AUC from time 0 to the last data point (AUC(0-tlast))(Up to 96 hours post-dose)
- Time to reach Cmax (tmax)(Up to 96 hours post-dose)
- Mean residence time (MRT)(Up to 96 hours post-dose)
- Percent amount excreted into urine from 0 to 96 h (end of urine sampling) after study drug administration (%AE,ur)(Up to 96 hours post-dose)
- Renal body clearance of drug (CLR)(Up to 96 hours post-dose)
- Total body clearance of unbound drug from plasma calculated after oral administration (apparent oral unbound clearance) (CLu/F)(Up to 96 hours post-dose)
- Amount excreted into urine from 0 to 96 h (end of urine sampling) after study drug administration (AE,ur)(Up to 96 hours post-dose)
- Number of participants with adverse events(Approximately 5 weeks)