Transporter Profiling Study for P-glycoprotein 1 (P-gp), Organic Anion Transporter 1 (OAT1), Organic Anion Transporter 3 (OAT3), Organic Cation Transporter 2 (OCT2), Multidrug and Toxin Extrusion Protein 1 (MATE1), Multidrug and Toxin Extrusion Protein 2-K (MATE2-K), Organic Anion Transporting Polypeptide 1B1 (OATP1B1), Organic Anion Transporting Polypeptide 1B3 (OATP1B3) and Breast Cancer Resistance Protein (BCRP) in Healthy Subjects and in Patients With Stage 4 (F4) Liver Fibrosis / Cirrhosis.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Area Under the Concentration Time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24)
研究概览
简要总结
This study is open to healthy adults and adults with liver cirrhosis. The purpose of this study is to compare how different medicines are handled by the body in people with and without liver cirrhosis. The study measures if the approved medicines rosuvastatin, digoxin, metformin, and furosemide are processed differently in people with liver cirrhosis than in people without liver cirrhosis.
This study will help to understand how new medicines being developed are handled by the body in people with liver cirrhosis. There are 3 groups in this study: people without liver cirrhosis, people with mild liver cirrhosis, and people with moderate liver cirrhosis. All participants get 1 dose each of rosuvastatin, digoxin, metformin, and furosemide by mouth. The participants with liver cirrhosis continue their regular treatment for the condition during the study.
Participants are in the study for about 1 month. During this time, they visit the study site 4 times. For 1 of the visits, they stay overnight for 2 nights at the study site. To assess the main study endpoint, the doctors take frequent blood samples from the participants. The doctors also regularly check participants' health and take note of any unwanted effects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Healthy subjects and F4 liver cirrhosis patients:
- •Signed and dated written informed consent in accordance with the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial
- •Either male subject, or female subject who meets any of the following criteria for a highly effective contraception from at least 30 days before the first administration of trial medication until 30 days after trial completion:
- •Use of combined (estrogen and progestogen containing) hormonal contraception that prevents ovulation (oral, intravaginal, or transdermal), plus condom
- •Use of progestogen-only hormonal contraception that inhibits ovulation (only injectables or implants), plus condom
- •Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
- •Sexually abstinent
- •A vasectomized sexual partner who received medical assessment of the surgical success (documented absence of sperm) and provided that the partner is the sole sexual partner of the trial participant
- •Surgically sterilized (including hysterectomy)
- •Postmenopausal, defined as no menses for 1 year without an alternative medical cause (in questionable cases a blood sample with levels of follicle-stimulating hormone (FSH) above 40 units per liter (U/L) and estradiol below 30 nanograms per liter (ng/L) is confirmatory)
- •Not taking any components in the cocktail within 4 weeks of enrolment
- •Healthy subjects only:
- •Healthy male or female subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests
- •Age of 18 to 75 years (inclusive)
- •Body mass index (BMI) of 18.5 to 35 kilograms per meter squared (kg/m2) (inclusive). A BMI of ≥ 30 is no exclusion criterion when the subject can be considered healthy apart from the elevated BMI
- •further inclusion criteria apply
- •F4 liver cirrhosis patients only:
- •Male and female subjects, 18 to 75 years
- •BMI of 18.5 to 40.0 kg/m2 (inclusive)
- •Stable treatment for at least 4 weeks prior to taking the cocktail
- •further inclusion criteria apply
- •Healthy subjects and F4 liver cirrhosis patients:
- •Subjects already taking digoxin, furosemide, metformin or rosuvastatin within 4 weeks of enrolment into the study. Furthermore, patients taking ezetimibe, fibrates, or the maximal dose (per Summary of Product Characteristics (SmPC)) of any statin are excluded from this study.
- •Subjects with any other condition that would preclude administration of digoxin, furosemide, metformin or rosuvastatin (i.e., contraindicated as per SmPC), such as hypersensitivity to active ingredient or any of the excipients or to sulphonamides, hypovolemia or dehydration, and partial obstructions of urinary outflow (e.g., prostatic hypertrophy)
- •Repeated measurement of systolic blood pressure outside the range of 90 to 150 millimeter of mercury (mmHg), diastolic blood pressure outside the range of 50 to 95 mmHg, or pulse rate outside the range of 60 to 90 beats per minute (bpm)
- •Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
- •Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders
- •History of relevant orthostatic hypotension, fainting spells, or blackouts
- •Relevant (other than Hepatitis B virus (HBV) or Hepatitis C virus (HCV)) chronic or acute infections (including an ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection)
- •Patients receiving antiviral therapy at the time of inclusion into the trial
排除标准
- 未提供
研究组 & 干预措施
Group 1: Healthy participants
Healthy participants received a single dose of the following cocktail on Day 1 after a standardized light breakfast and 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
干预措施: Rosuvastatin (Drug)
Group 1: Healthy participants
Healthy participants received a single dose of the following cocktail on Day 1 after a standardized light breakfast and 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
干预措施: Digoxin (Drug)
Group 1: Healthy participants
Healthy participants received a single dose of the following cocktail on Day 1 after a standardized light breakfast and 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
干预措施: Metformin hydrochlorid (Drug)
Group 1: Healthy participants
Healthy participants received a single dose of the following cocktail on Day 1 after a standardized light breakfast and 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
干预措施: Furosemide (Drug)
Group 2: F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated)
Patients with compensated liver cirrhosis due to any underlying liver disease with advanced fibrosis (F4) and hepatic impairment that meets the criteria for Child-Pugh A received a single dose of the following cocktail on Day 1 after a standardized light breakfast and with 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
Compensated=without any disease symptoms
干预措施: Rosuvastatin (Drug)
Group 2: F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated)
Patients with compensated liver cirrhosis due to any underlying liver disease with advanced fibrosis (F4) and hepatic impairment that meets the criteria for Child-Pugh A received a single dose of the following cocktail on Day 1 after a standardized light breakfast and with 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
Compensated=without any disease symptoms
干预措施: Digoxin (Drug)
Group 2: F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated)
Patients with compensated liver cirrhosis due to any underlying liver disease with advanced fibrosis (F4) and hepatic impairment that meets the criteria for Child-Pugh A received a single dose of the following cocktail on Day 1 after a standardized light breakfast and with 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
Compensated=without any disease symptoms
干预措施: Metformin hydrochlorid (Drug)
Group 2: F4 Child-Turcotte-Pugh class A (Child-Pugh A) subjects (compensated)
Patients with compensated liver cirrhosis due to any underlying liver disease with advanced fibrosis (F4) and hepatic impairment that meets the criteria for Child-Pugh A received a single dose of the following cocktail on Day 1 after a standardized light breakfast and with 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
Compensated=without any disease symptoms
干预措施: Furosemide (Drug)
Group 3: F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (decompensated)
Patients with decompensated liver cirrhosis due to any underlying liver disease with advanced fibrosis (F4) and hepatic impairment that met the criteria for Child-Pugh B received a single dose of the following cocktail on Day 1 after a standardized light breakfast and with 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
Decompensated= with disease symptoms like aszites, variceal bleeding, hepatic encephalopathy, hepato-renal syndrome
干预措施: Rosuvastatin (Drug)
Group 3: F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (decompensated)
Patients with decompensated liver cirrhosis due to any underlying liver disease with advanced fibrosis (F4) and hepatic impairment that met the criteria for Child-Pugh B received a single dose of the following cocktail on Day 1 after a standardized light breakfast and with 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
Decompensated= with disease symptoms like aszites, variceal bleeding, hepatic encephalopathy, hepato-renal syndrome
干预措施: Digoxin (Drug)
Group 3: F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (decompensated)
Patients with decompensated liver cirrhosis due to any underlying liver disease with advanced fibrosis (F4) and hepatic impairment that met the criteria for Child-Pugh B received a single dose of the following cocktail on Day 1 after a standardized light breakfast and with 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
Decompensated= with disease symptoms like aszites, variceal bleeding, hepatic encephalopathy, hepato-renal syndrome
干预措施: Metformin hydrochlorid (Drug)
Group 3: F4 Child-Turcotte-Pugh class B (Child-Pugh B) subjects (decompensated)
Patients with decompensated liver cirrhosis due to any underlying liver disease with advanced fibrosis (F4) and hepatic impairment that met the criteria for Child-Pugh B received a single dose of the following cocktail on Day 1 after a standardized light breakfast and with 280 ml of water: 0.25 milligrams (mg) digoxin as tablet, 1 mg furosemide as 0.1 milliliters (ml) oral solution, 10 mg metformin hydrochloride as 0.05 ml oral solution and 10 mg rosuvastatin as film-coated tablet.
Decompensated= with disease symptoms like aszites, variceal bleeding, hepatic encephalopathy, hepato-renal syndrome
干预措施: Furosemide (Drug)
结局指标
主要结局
Area Under the Concentration Time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24)
时间窗: Within 2 hours (hrs) before and at 30 minutes (min), 1 hrs, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs, 12 hrs, and 24 hrs after drug administration.
Adjusted geometric means and adjusted geometric standard errors were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetics endpoint was log transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: 'group', age, and BMI. All effects were considered as fixed.
Maximum Measured Concentration of Rosuvastatin in Plasma (Cmax)
时间窗: Within 2 hours (hrs) before and at 30 minutes (min), 1 hrs, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs, 12 hrs, and 24 hrs after drug administration.
Adjusted geometric means and adjusted geometric standard errors were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetics endpoint was log transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: 'group', age, and BMI. All effects were considered as fixed.
Area Under the Concentration Time Curve of Digoxin in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24)
时间窗: Within 2 hours (hrs) before and at 30 minutes (min), 1 hrs, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs, 12 hrs, and 24 hrs after drug administration.
Adjusted geometric means and adjusted geometric standard errors were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetics endpoint was log transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: 'group', age, and BMI. All effects were considered as fixed.
Maximum Measured Concentration of Digoxin in Plasma (Cmax)
时间窗: Within 2 hours (hrs) before and at 30 minutes (min), 1 hrs, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs, 12 hrs, and 24 hrs after drug administration.
Adjusted geometric means and adjusted geometric standard errors were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetics endpoint was log transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: 'group', age, and BMI. All effects were considered as fixed.
Area Under the Concentration Time Curve of Metformin in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24)
时间窗: Within 2 hours (hrs) before and at 30 minutes (min), 1 hrs, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs, 12 hrs, and 24 hrs after drug administration.
Adjusted geometric means and adjusted geometric standard errors were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetics endpoint was log transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: 'group', age, and BMI. All effects were considered as fixed.
Maximum Measured Concentration of Metformin in Plasma (Cmax)
时间窗: Within 2 hours (hrs) before and at 30 minutes (min), 1 hrs, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs, 12 hrs, and 24 hrs after drug administration.
Adjusted geometric means and adjusted geometric standard errors were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetics endpoint was log transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: 'group', age, and BMI. All effects were considered as fixed.
Area Under the Concentration Time Curve of Furosemide in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24)
时间窗: Within 2 hours (hrs) before and at 30 minutes (min), 1 hrs, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs, 12 hrs, and 24 hrs after drug administration.
Adjusted geometric means and adjusted geometric standard errors were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetics endpoint was log transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: 'group', age, and BMI. All effects were considered as fixed.
Maximum Measured Concentration of Furosemide in Plasma (Cmax)
时间窗: Within 2 hours (hrs) before and at 30 minutes (min), 1 hrs, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, 10 hrs, 12 hrs, and 24 hrs after drug administration.
Adjusted geometric means and adjusted geometric standard errors were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetics endpoint was log transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: 'group', age, and BMI. All effects were considered as fixed.
次要结局
未报告次要终点