Healthy
Conditions
Brief summary
The primary objective of this trial is to investigate the relative bioavailabilities of digoxin, furosemide, metformin and rosuvastatin given as a cocktail alone and as a cocktail together with the following drug transporter inhibitors: Part 1: verapamil (P-gp) and rifampin (OATP1B1/1B3) Part 2: cimetidine (OCT2/MATE) Part 3: probenecid (OAT1/3) The secondary objective is to investigate other potential changes in pharmacokinetics (e.g. in clearance, volume of distribution, etc.) of digoxin, furosemide, metformin and rosuvastatin given as a cocktail alone and as a cocktail together with the inhibitors describe above.
Interventions
DRUGDigoxin
Tablet
DRUGFurosemide
Oral solution
DRUGMetformin
Oral solution
DRUGRosuvastatin
Film-coated tablet
DRUGVerapamil
Film-coated tablet
DRUGRifampin
Film-coated tablet
DRUGCimetidine
Tablet
DRUGProbenecid
Tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male subjects according to the investigator's assessment, 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 55 years (incl.) * Body Mass Index (BMI) of 18.5 to 29.9 kg/m2 (incl.) * Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
* Any finding in the medical examination (including Blood Pressure (BP), Pulse Rate (PR) or Electrocardiogram (ECG)) is deviating from normal and judged as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and 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 * Chronic or relevant acute infections * History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients, sulphonamides, or cardiac glycosides) * Use of drugs within 30 days prior to administration of trial medication if that might reasonably influence the results of the trial (incl. QT/QTc interval prolongation) * Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication, or current participation in another trial involving administration of investigational drug * Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) * Inability to refrain from smoking on specified trial days * Alcohol abuse (consumption of more than 24 g per day for males) * Drug abuse or positive drug screening * Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial * Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial * Inability to comply with dietary regimen of trial site * Subject is assessed as unsuitable for inclusion by the investigator, for instance, because considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study * Male subjects with Women of child bearing potential (WOCBP) partner who are unwilling to use male contraception (condom or sexual abstinence) from the first administration of trial medication until 30 days after last administration of trial medication * Hypokalemia, hypomagnesemia, or hypercalcemia * PQ interval greater than 220 ms in the Electrocardiogram (ECG) at screening * Marked conductivity disorders (e.g. sinu-atrial blocks of II° or III°) * Myopathy * Hereditary galactose or fructose intolerance, lactase deficiency, or glucose-galactose malabsorption * History of nephrolithiasis * Gout or clinically relevant elevation of uric acid * Creatinine clearance (according to CKD EPI formula) is lower than 80 ml/min * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE. |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. gMean presented here is an adjusted gMean and SE presented is a gSE. |
| Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE. |
| Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE. |
| Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE. |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1) | Samples were taken within 0:20 hour:minutes (hh:mm) prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. Geometric mean (gMean) presented here is an adjusted gMean and standard error (SE) presented is a geometric SE (gSE). |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. gMean presented here is an adjusted gMean and SE presented is a gSE. |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. gMean presented here is an adjusted gMean and SE presented is a gSE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T2 vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | AUC0-∞, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 extrapolated to infinity is presented. AUC0-∞ not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE. |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T3 vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | AUC0-∞, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 extrapolated to infinity is presented. AUC0-∞ not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE. |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T4 vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | AUC0-∞, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 extrapolated to infinity is presented. AUC0-∞ not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE. |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T1 vs. R1) | Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration. | AUC0-∞, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 extrapolated to infinity is presented. AUC0-∞ not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE. |
Countries
Germany
Participant flow
Recruitment details
The trial consisted of 3 parts investigating different drug transporter inhibitors. All parts of the trial were performed in healthy male participants in a randomised, open-label, three-way (Part 1) or four-way (Part 2 and 3) crossover design.
Pre-assignment details
All participants were screened for eligibility to participate in the trial. Participants were not to be randomised to trial treatment if any of the in- or exclusion criteria were violated at screening.
Participants by arm
| Arm | Count |
|---|---|
| Cocktail (R1)/ (Verapamil + R1)/ (Rifampin + R1) In trial part 1 participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 milliliter (mL) of water in period 1. R1 is a drug cocktail that contains a single dose of each, 0.25 milligram (mg) Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet. Followed by a single dose of 120 mg Verapamil orally with 240 mL of water at 1 hour (h) prior to R1 which is administered with 280 mL of water in period 2. In period 3 participants were administered a single dose of 600 mg Rifampin film-coated tablet with 280 mL of water together with R1. Treatment periods were separated by a wash-out period of 13 days. | 4 |
| (Verapamil + R1)/ (Rifampin + R1)/ R1 In trial part 1 participants were administered a single dose of 120 mg Verapamil orally with 240 mL of water at 1 h prior to R1 which is administered with 280 mL of water in period 1. Followed by a single dose of 600 mg Rifampin film-coated tablet orally with 280 mL of water together with R1 in period 2. In period 3 participants were administered a single dose of R1 with 280 milliliter (mL) of water. R1 is a drug cocktail that contains a single dose of each, 0.25 milligram (mg) Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet. Treatment periods were separated by a wash-out period of 13 days. | 4 |
| (Rifampin + R1)/ R1/ (Verapamil + R1) In trial part 1 participants were administered a single dose of 600 mg Rifampin film-coated tablet orally with 280 mL of water together with R1 in period 1. Followed by a single dose of R1 with 280 mL of water in period 2. R1 is a drug cocktail that contains a single dose of each, 0.25 mg Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet. In period 3 participants were administered a single dose of 120 mg Verapamil orally with 240 mL of water at 1 hour (h) prior to the R1 which is administered with 280 mL of water. Treatment periods were separated by a wash-out period of 13 days. | 4 |
| R1/ Metformin/ (Cimetidine+R1)/ (Cimetidine+Metformin) In trial part 2 participants were administered single dose of R1 which is administered with 280 mL of water in period 1. R1 is a drug cocktail that contains a single dose of each 0.25 milligram (mg) Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet. Followed by single therapeutic dose of 500 mg Metformin oral solution with 280 mL of water in period 2. Followed by 400 mg Cimetidine 1 orally at 1 h prior to R1 and at 4 h, 8 h, 12 h, 24 h (Day 2) and 36 h after R1 (Day 2) in period 3. Followed by 400 mg Cimetidine 1 tablet orally at 1 h prior to therapeutic dose of 500mg of Metformin and at 4 h, 8 h, 12, 24 h (Day 2) and 36 h after metformin (Day 2) in period 4. All doses of Cimetidine administered with 240 mL water and R1 and dose of Metformin with 280 mL of water. Treatment periods were separated by a wash-out period of at least 7 days. | 4 |
| Metformin/ (Cimetidine+Metformin)/ R1/ (Cimetidine+R1) In trial part 2 participants were administered single therapeutic dose of 500 mg Metformin oral solution with 280 mL of water in period 1. Followed by 400 mg Cimetidine 1 tablet orally at 1 h prior to Metformin and at 4 h, 8 h, 12, 24 h (Day 2) and 36 h after metformin (Day 2) in period 2. Followed by a single dose of R1 with 280 mL of water in period 3. R1 is a drug cocktail that contains single dose of each 0.25 milligram (mg) Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet. Followed by 400 mg Cimetidine 1 orally at 1 h prior to R1 and at 4 h, 8 h, 12 h, 24 h (Day 2) and 36 h after R1 (Day 2) in period 4. All doses of Cimetidine administered with 240 mL water and R1 and dose of Metformin with 280 mL of water. Treatment periods were separated by a wash-out period of at least 7 days. | 4 |
| (Cimetidine+R1)/ R1/ (Cimetidine+Metformin)/ Metformin In trial part 2 participants were administered 400 mg Cimetidine 1 tablet orally at 1 h prior to R1 and at 4 h, 8 h, 12 h, 24 h (Day 2) and 36 h after R1 (Day 2) in period 1. Followed by single dose of R1 which is administered with 280 mL of water in period 1. R1 is a drug cocktail that contains single dose of each 0.25 mg Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet in period 2. Followed by 400 mg Cimetidine 1 tablet orally at 1 h prior to Metformin and at 4 h, 8 h, 12, 24 h (Day 2) and 36 h after Metformin (Day 2) in period 3. Followed by single therapeutic dose of 500 mg Metformin oral solution with 280 mL of water in period 4. All doses of Cimetidine administered with 240 mL water and R1 and dose of Metformin with 280 mL of water. Treatment periods were separated by a wash-out period of at least 7 days. | 4 |
| (Cimetidine+Metformin)/ (Cimetidine+R1)/ Metformin/ R1 In trial part 2 participants were administered 400 mg Cimetidine 1 tablet orally at 1 h prior to Metformin and at 4 h, 8 h, 12, 24 h (Day 2) and 36 h after Metformin (Day 2) in period 1. Followed by 400 mg Cimetidine 1 tablet orally at 1 h prior to R1 and at 4 h, 8 h, 12 h, 24 h (Day 2) and 36 h after R1 (Day 2) in period 2. Followed by single therapeutic dose of 500 mg Metformin oral solution with 280 mL of water in period 3. Followed by single dose of R1 which is administered with 280 mL of water in period 1. R1 is a drug cocktail that contains single dose of each 0.25 mg Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet in period 4. All doses of Cimetidine administered with 240 mL water and R1 and dose of Metformin with 280 mL of water. Treatment periods were separated by a wash-out period of at least 7 days. | 5 |
| R1/ Furosemide/ (Probenecid + R1)/ (Probenecid + Furosemide) In trial part 3 participants were administered single dose of R1 which is administered with 280 mL of water in period 1. R1 is a drug cocktail that contains single dose of each 0.25 mg Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet. Followed by single therapeutic dose of 40 mg Furosemide oral solution with 280 mL of water in period 2. Followed by 2 tablets of 500 mg Probenecid (2\*500 mg) administered orally 13 h prior and again 1 h prior to the administration of R1 on day 1 in period 3. Followed by 2 tablets of 500 mg Probenecid (2\*500 mg) administered orally 13 hours prior and again 1 h prior to the administration of Furosemide on Day 1 in period 4. All doses of Cimetidine administered with 240 mL water and dose of Furosemide and R1 with 280 mL of water. Treatment periods were separated by a wash-out period of at least 7 days. | 4 |
| Furosemide/ (Probenecid + Furosemide)/ R1/ (Probenecid + R1) In trial part 3 participants were administered single therapeutic dose of 40 mg Furosemide oral solution with 280 mL of water in period 1. Followed by 2 tablets of 500 mg Probenecid (2\*500 mg) administered orally 13 hours prior and again 1 h prior to the administration of Furosemide on Day 1 in period 2. Followed by single dose of R1 which is administered with 280 milliliter (mL) of water in period 3. R1 is a drug cocktail that contains single dose of each 0.25 milligram (mg) Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet. Followed by 2 tablets of 500 mg Probenecid (2\*500 mg) administered orally 13 h prior and again 1 h prior to the administration of R1 on day 1 in period 4. All doses of Cimetidine administered with 240 mL water and dose of Furosemide and R1 with 280 mL of water. Treatment periods were separated by a wash-out period of at least 7 days. | 4 |
| (Probenecid + R1)/ R1/ (Probenecid + Furosemide)/ Furosemide In trial part 3 participants were administered 2 tablets of 500 mg Probenecid (2\*500 mg) administered orally 13 h prior and again 1 h prior to the administration of R1 on day 1 in period 1. Followed by single dose of R1 which is administered with 280 mL of water in period 2. R1 is a drug cocktail that contains single dose of each 0.25 mg Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet. Followed by 2 tablets of 500 mg Probenecid (2\*500 mg) administered orally 13 hours prior and again 1 h prior to the administration of Furosemide on Day 1 in period 3. Followed by single therapeutic dose of 40 mg Furosemide oral solution with 280 mL of water in period 4. All doses of Cimetidine administered with 240 mL water and dose of Furosemide and R1 with 280 mL of water. Treatment periods were separated by a wash-out period of at least 7 days. | 4 |
| (Probenecid + Furosemide)/ (Probenecid + R1)/ Furosemide/ R1 In trial part 3 participants were administered 2 tablets of 500 mg Probenecid (2\*500 mg) administered orally 13 hours prior and again 1 h prior to the administration of Furosemide on Day 1 in period 1. Followed by 2 tablets of 500 mg Probenecid (2\*500 mg) administered orally 13 h prior and again 1 h prior to the administration of R1 on day 1 in period 2. Followed by single therapeutic dose of 40 mg Furosemide oral solution with 280 mL of water in period 3. Followed by single dose of R1 which is administered with 280 milliliter (mL) of water in period 4. R1 is a drug cocktail that contains a single dose of each 0.25 milligram (mg) Digoxin tablet, 1 mg Furosemide oral solution, 10 mg Metformin oral solution and 10 mg Rosuvastatin film-coated tablet. All doses of Cimetidine administered with 240 mL water and dose of Furosemide and R1 with 280 mL of water. Treatment periods were separated by a wash-out period of at least 7 days. | 4 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 2, Period 1 | Treatment not received | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Part 2, Period 3 | Other than listed | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 2, Period 4 | Other than listed | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 3, Washout Period 3 (7 Days) | Treatment not received due to AE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cocktail (R1)/ (Verapamil + R1)/ (Rifampin + R1) | (Verapamil + R1)/ (Rifampin + R1)/ R1 | (Rifampin + R1)/ R1/ (Verapamil + R1) | R1/ Metformin/ (Cimetidine+R1)/ (Cimetidine+Metformin) | Metformin/ (Cimetidine+Metformin)/ R1/ (Cimetidine+R1) | (Cimetidine+R1)/ R1/ (Cimetidine+Metformin)/ Metformin | (Cimetidine+Metformin)/ (Cimetidine+R1)/ Metformin/ R1 | R1/ Furosemide/ (Probenecid + R1)/ (Probenecid + Furosemide) | Furosemide/ (Probenecid + Furosemide)/ R1/ (Probenecid + R1) | (Probenecid + R1)/ R1/ (Probenecid + Furosemide)/ Furosemide | (Probenecid + Furosemide)/ (Probenecid + R1)/ Furosemide/ R1 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Part 1 | 30.0 Years STANDARD_DEVIATION 6.8 | 51.5 Years STANDARD_DEVIATION 1.3 | 36.3 Years STANDARD_DEVIATION 10.6 | 32.8 Years STANDARD_DEVIATION 10.2 | 38.3 Years STANDARD_DEVIATION 13.1 | 35.3 Years STANDARD_DEVIATION 11.1 | 41.6 Years STANDARD_DEVIATION 10.5 | 29.3 Years STANDARD_DEVIATION 7.9 | 30.0 Years STANDARD_DEVIATION 8.8 | 33.0 Years STANDARD_DEVIATION 13.2 | 43.5 Years STANDARD_DEVIATION 8.1 | 36.6 Years STANDARD_DEVIATION 10.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 3 Participants | 5 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 44 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 12 | 0 / 12 | 0 / 16 | 0 / 17 | 0 / 17 | 0 / 16 | 0 / 16 | 0 / 15 |
| other Total, other adverse events | 5 / 42 | 1 / 12 | 2 / 12 | 7 / 16 | 7 / 17 | 7 / 17 | 4 / 16 | 4 / 16 | 3 / 15 |
| serious Total, serious adverse events | 0 / 42 | 0 / 12 | 0 / 12 | 0 / 16 | 0 / 17 | 0 / 17 | 0 / 16 | 0 / 16 | 0 / 15 |
Outcome results
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1)
AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1) | Digoxin | 19.03 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.07 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1) | Furosemide | 196.39 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1) | Metformin | 2006.60 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1) | Rosuvastatin | 139.54 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.13 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1) | Rosuvastatin | 129.90 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.13 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1) | Digoxin | 15.15 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.07 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1) | Metformin | 1532.41 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.07 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1) | Furosemide | 194.05 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
90% CI: [113.99, 138.43]ANOVA
90% CI: [94.59, 108.3]ANOVA
90% CI: [119.82, 143.1]ANOVA
90% CI: [97.57, 118.27]ANOVA
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1)
AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1) | Digoxin | 14.44 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.08 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1) | Furosemide | 483.38 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.08 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1) | Metformin | 1331.83 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.08 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1) | Rosuvastatin | 238.16 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1) | Rosuvastatin | 106.69 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1) | Digoxin | 13.52 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.08 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1) | Metformin | 1321.20 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.08 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1) | Furosemide | 177.96 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.07 |
90% CI: [96.51, 118.15]ANOVA
90% CI: [246.74, 299.03]ANOVA
90% CI: [94.62, 107.39]ANOVA
90% CI: [203.79, 244.55]ANOVA
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1)
AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1) | Furosemide | 211.82 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1) | Digoxin | 17.89 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1) | Metformin | 1473.38 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1) | Rosuvastatin | 303.81 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.11 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1) | Rosuvastatin | 87.29 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.11 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1) | Digoxin | 13.61 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1) | Furosemide | 176.85 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1) | Metformin | 1357.34 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
90% CI: [115.93, 148.97]ANOVA
90% CI: [110.03, 130.39]ANOVA
90% CI: [100.68, 117.03]ANOVA
90% CI: [299.64, 404.31]ANOVA
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1)
AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. Geometric mean (gMean) presented here is an adjusted gMean and standard error (SE) presented is a geometric SE (gSE).
Time frame: Samples were taken within 0:20 hour:minutes (hh:mm) prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): All subjects in the TS providing at least 1 primary or secondary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1) | Digoxin | 13.71 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1) | Furosemide | 165.80 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1) | Metformin | 1126.22 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1) | Rosuvastatin | 98.98 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.11 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1) | Rosuvastatin | 87.29 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.11 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1) | Digoxin | 13.61 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1) | Metformin | 1357.34 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1) | Furosemide | 176.85 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
90% CI: [86.12, 102.06]ANOVA
90% CI: [76.96, 89.46]ANOVA
90% CI: [97.62, 131.72]ANOVA
90% CI: [88.84, 114.15]ANOVA
Primary
Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1)
Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1) | Digoxin | 1.42 Nanomole/ litre (nmol/ L) | Standard Error 1.09 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1) | Furosemide | 84.32 Nanomole/ litre (nmol/ L) | Standard Error 1.06 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1) | Metformin | 179.45 Nanomole/ litre (nmol/ L) | Standard Error 1.04 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1) | Rosuvastatin | 7.90 Nanomole/ litre (nmol/ L) | Standard Error 1.14 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1) | Rosuvastatin | 6.84 Nanomole/ litre (nmol/ L) | Standard Error 1.14 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1) | Digoxin | 1.17 Nanomole/ litre (nmol/ L) | Standard Error 1.09 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1) | Metformin | 223.78 Nanomole/ litre (nmol/ L) | Standard Error 1.04 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1) | Furosemide | 88.59 Nanomole/ litre (nmol/ L) | Standard Error 1.06 |
90% CI: [100.43, 147.33]ANOVA
90% CI: [83.03, 109.11]ANOVA
90% CI: [73.01, 88.08]ANOVA
90% CI: [93.8, 141.94]ANOVA
Primary
Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1)
Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1) | Digoxin | 2.55 Nanomole/ litre (nmol/ L) | Standard Error 1.09 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1) | Furosemide | 119.66 Nanomole/ litre (nmol/ L) | Standard Error 1.06 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1) | Metformin | 251.32 Nanomole/ litre (nmol/ L) | Standard Error 1.04 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1) | Rosuvastatin | 77.00 Nanomole/ litre (nmol/ L) | Standard Error 1.14 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1) | Rosuvastatin | 6.84 Nanomole/ litre (nmol/ L) | Standard Error 1.14 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1) | Digoxin | 1.17 Nanomole/ litre (nmol/ L) | Standard Error 1.09 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1) | Metformin | 223.78 Nanomole/ litre (nmol/ L) | Standard Error 1.04 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1) | Furosemide | 88.59 Nanomole/ litre (nmol/ L) | Standard Error 1.06 |
90% CI: [180.19, 264.36]ANOVA
90% CI: [117.83, 154.84]ANOVA
90% CI: [102.26, 123.35]ANOVA
90% CI: [914.63, 1384]ANOVA
Primary
Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1)
Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1) | Digoxin | 1.65 Nanomole/ litre (nmol/ L) | Standard Error 1.07 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1) | Furosemide | 97.69 Nanomole/ litre (nmol/ L) | Standard Error 1.08 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1) | Metformin | 316.83 Nanomole/ litre (nmol/ L) | Standard Error 1.07 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1) | Rosuvastatin | 13.21 Nanomole/ litre (nmol/ L) | Standard Error 1.15 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1) | Rosuvastatin | 11.30 Nanomole/ litre (nmol/ L) | Standard Error 1.15 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1) | Digoxin | 1.35 Nanomole/ litre (nmol/ L) | Standard Error 1.08 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1) | Metformin | 258.33 Nanomole/ litre (nmol/ L) | Standard Error 1.08 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1) | Furosemide | 93.23 Nanomole/ litre (nmol/ L) | Standard Error 1.08 |
90% CI: [180.19, 264.36]ANOVA
90% CI: [89.97, 122.03]ANOVA
90% CI: [107.68, 139.69]ANOVA
90% CI: [105.07, 130.03]ANOVA
Primary
Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1)
Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1) | Digoxin | 1.13 Nanomole/ litre (nmol/ L) | Standard Error 1.07 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1) | Furosemide | 110.64 Nanomole/ litre (nmol/ L) | Standard Error 1.07 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1) | Metformin | 246.78 Nanomole/ litre (nmol/ L) | Standard Error 1.12 |
| Verapamil + R1 (T1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1) | Rosuvastatin | 43.29 Nanomole/ litre (nmol/ L) | Standard Error 1.11 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1) | Rosuvastatin | 10.11 Nanomole/ litre (nmol/ L) | Standard Error 1.1 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1) | Digoxin | 1.30 Nanomole/ litre (nmol/ L) | Standard Error 1.07 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1) | Metformin | 243.49 Nanomole/ litre (nmol/ L) | Standard Error 1.12 |
| Cocktail (R1) | Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1) | Furosemide | 90.00 Nanomole/ litre (nmol/ L) | Standard Error 1.07 |
90% CI: [76.08, 99.64]ANOVA
90% CI: [110.25, 137.09]ANOVA
90% CI: [93.65, 109.7]ANOVA
90% CI: [359.78, 509.7]ANOVA
Secondary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T1 vs. R1)
AUC0-∞, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 extrapolated to infinity is presented. AUC0-∞ not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T1 vs. R1) | Metformin | 1147.23 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T1 vs. R1) | Furosemide | 176.44 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T1 vs. R1) | Rosuvastatin | 116.80 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T1 vs. R1) | Furosemide | 191.29 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T1 vs. R1) | Metformin | 1365.85 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T1 vs. R1) | Rosuvastatin | 94.14 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
90% CI: [85.28, 99.76]ANOVA
90% CI: [78.32, 90.08]ANOVA
90% CI: [105.11, 146.43]ANOVA
Secondary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T2 vs. R1)
AUC0-∞, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 extrapolated to infinity is presented. AUC0-∞ not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T2 vs. R1) | Furosemide | 215.63 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T2 vs. R1) | Metformin | 1482.76 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T2 vs. R1) | Rosuvastatin | 320.72 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T2 vs. R1) | Furosemide | 191.29 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T2 vs. R1) | Metformin | 1365.85 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T2 vs. R1) | Rosuvastatin | 94.14 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
90% CI: [104.23, 121.92]ANOVA
90% CI: [101.22, 116.43]ANOVA
90% CI: [288.63, 402.1]ANOVA
Secondary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T3 vs. R1)
AUC0-∞, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 extrapolated to infinity is presented. AUC0-∞ not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T3 vs. R1) | Furosemide | 202.17 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.04 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T3 vs. R1) | Metformin | 2023.33 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.06 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T3 vs. R1) | Rosuvastatin | 148.32 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.13 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T3 vs. R1) | Furosemide | 200.61 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.05 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T3 vs. R1) | Metformin | 1540.21 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.07 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T3 vs. R1) | Rosuvastatin | 139.21 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.13 |
90% CI: [93.59, 108.51]ANOVA
90% CI: [120.37, 143.37]ANOVA
90% CI: [96.87, 117.19]ANOVA
Secondary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T4 vs. R1)
AUC0-∞, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 extrapolated to infinity is presented. AUC0-∞ not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE.
Time frame: Samples were taken within 0:20 hh:mm prior to first study drug administration and at 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 11:00, 12:00, 24:00, 36:00, 47:00, 71:00 and 95:00 after drug administration.
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T4 vs. R1) | Furosemide | 489.28 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.07 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T4 vs. R1) | Metformin | 1346.62 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.08 |
| Verapamil + R1 (T1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T4 vs. R1) | Rosuvastatin | 244.94 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T4 vs. R1) | Furosemide | 188.11 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.07 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T4 vs. R1) | Metformin | 1330.47 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.07 |
| Cocktail (R1) | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T4 vs. R1) | Rosuvastatin | 113.78 Nanomole*hour/litre (nmol*h/L) | Standard Error 1.1 |
90% CI: [237.96, 284.32]ANOVA
90% CI: [95.15, 107.66]ANOVA
90% CI: [197.53, 234.63]ANOVA