This Study Tests the Effect of Certain Medicines on the Transport of Other Medicines in the Body of Healthy Men

Sponsor

Boehringer Ingelheim (Industry)

Overall Status

Completed

CT.gov ID

NCT03307252

Collaborator

(none)

Enrollment

Location

Arms

6.2

Actual Duration (Months)

7.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Digoxin Drug: Furosemide Drug: Metformin Drug: Rosuvastatin Drug: Verapamil Drug: Rifampin Drug: Cimetidine Drug: Probenecid	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

45 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

The Effect of Potent Inhibitors of Drug Transporters (Verapamil, Rifampin, Cimetidine, Probenecid) on Pharmacokinetics of a Transporter Probe Drug Cocktail Consisting of Digoxin, Furosemide, Metformin and Rosuvastatin (an Open-label, Randomised, Crossover Trial in Three Parts)

Actual Study Start Date :

Oct 25, 2017

Actual Primary Completion Date :

May 2, 2018

Actual Study Completion Date :

May 2, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Reference 1	Drug: Digoxin Tablet Drug: Furosemide Oral solution Drug: Metformin Oral solution Drug: Rosuvastatin Film-coated tablet
Experimental: Treatment Reference 2	Drug: Metformin Oral solution
Experimental: Treatment Reference 3	Drug: Furosemide Oral solution
Experimental: Treatment 1	Drug: Digoxin Tablet Drug: Furosemide Oral solution Drug: Metformin Oral solution Drug: Rosuvastatin Film-coated tablet Drug: Verapamil Film-coated tablet
Experimental: Treatment 2	Drug: Digoxin Tablet Drug: Furosemide Oral solution Drug: Metformin Oral solution Drug: Rosuvastatin Film-coated tablet Drug: Rifampin Film-coated tablet
Experimental: Treatment 3	Drug: Digoxin Tablet Drug: Furosemide Oral solution Drug: Metformin Oral solution Drug: Rosuvastatin Film-coated tablet Drug: Cimetidine Tablet
Experimental: Treatment 4	Drug: Digoxin Tablet Drug: Furosemide Oral solution Drug: Metformin Oral solution Drug: Rosuvastatin Film-coated tablet Drug: Probenecid Tablet
Experimental: Treatment 5	Drug: Metformin Oral solution Drug: Cimetidine Tablet
Experimental: Treatment 6	Drug: Furosemide Oral solution Drug: Probenecid Tablet

Outcome Measures

Primary Outcome Measures

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.
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.
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.

Secondary Outcome Measures

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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

Male

Accepts 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 exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CTC North GmbH & Co. KG, Hamburg	Hamburg		Germany	20251

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

None specified.

Study Documents (Full-Text)

More Information

Additional Information:

Related Info

Publications

None provided.

Responsible Party:

Boehringer Ingelheim

ClinicalTrials.gov Identifier:

NCT03307252

Other Study ID Numbers:

0352-2100
2017-001549-29

First Posted:

Oct 11, 2017

Last Update Posted:

Jul 12, 2019

Last Verified:

Apr 1, 2019

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Study Results

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 Detail	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.

Arm/Group Title	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
Arm/Group Description	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.	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.	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.	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.	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.	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.	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.	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 (2500 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 (2500 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.	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 (2500 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 (2500 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.	In trial part 3 participants were administered 2 tablets of 500 mg Probenecid (2500 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 (2500 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.	In trial part 3 participants were administered 2 tablets of 500 mg Probenecid (2500 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 (2500 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.
Period Title: Part 1, Period 1
STARTED	4	4	4	0	0	0	0	0	0	0	0
COMPLETED	4	4	4	0	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	4	4	4	0	0	0	0	0	0	0	0
COMPLETED	4	4	4	0	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	4	4	4	0	0	0	0	0	0	0	0
COMPLETED	4	4	4	0	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	4	4	4	0	0	0	0	0	0	0	0
COMPLETED	4	4	4	0	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	4	4	4	0	0	0	0	0	0	0	0
COMPLETED	4	4	4	0	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	4	4	4	5	0	0	0	0
COMPLETED	0	0	0	4	4	3	5	0	0	0	0
NOT COMPLETED	0	0	0	0	0	1	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	4	4	3	5	0	0	0	0
COMPLETED	0	0	0	4	4	3	5	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	4	4	3	5	0	0	0	0
COMPLETED	0	0	0	4	4	3	5	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	4	4	3	5	0	0	0	0
COMPLETED	0	0	0	4	4	3	5	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	4	4	3	5	0	0	0	0
COMPLETED	0	0	0	4	3	3	5	0	0	0	0
NOT COMPLETED	0	0	0	0	1	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	4	3	3	5	0	0	0	0
COMPLETED	0	0	0	4	3	3	4	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	1	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	4	3	3	5	0	0	0	0
COMPLETED	0	0	0	4	3	3	4	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	1	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	0	0	0	0	4	4	4	4
COMPLETED	0	0	0	0	0	0	0	4	4	4	4
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	0	0	0	0	4	4	4	4
COMPLETED	0	0	0	0	0	0	0	4	4	4	4
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	0	0	0	0	4	4	4	4
COMPLETED	0	0	0	0	0	0	0	4	4	4	4
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	0	0	0	0	4	4	4	4
COMPLETED	0	0	0	0	0	0	0	4	4	4	4
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	0	0	0	0	4	4	4	4
COMPLETED	0	0	0	0	0	0	0	4	4	4	4
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0
Period Title: Part 1, Period 1
STARTED	0	0	0	0	0	0	0	4	4	4	4
COMPLETED	0	0	0	0	0	0	0	4	4	4	3
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	1
Period Title: Part 1, Period 1
STARTED	0	0	0	0	0	0	0	4	4	4	3
COMPLETED	0	0	0	0	0	0	0	4	4	4	3
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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.	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.	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.	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.	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.	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.	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.	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 (2500 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 (2500 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.	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 (2500 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 (2500 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.	In trial part 3 participants were administered 2 tablets of 500 mg Probenecid (2500 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 (2500 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.	In trial part 3 participants were administered 2 tablets of 500 mg Probenecid (2500 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 (2500 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.	Total of all reporting groups
Overall Participants	4	4	4	4	4	4	5	4	4	4	4	45
Age (Years) [Mean (Standard Deviation) ]
Part 1	30.0 (6.8)	51.5 (1.3)	36.3 (10.6)	32.8 (10.2)	38.3 (13.1)	35.3 (11.1)	41.6 (10.5)	29.3 (7.9)	30.0 (8.8)	33.0 (13.2)	43.5 (8.1)	36.6 (10.8)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	4 100%	4 100%	4 100%	4 100%	4 100%	4 100%	5 100%	4 100%	4 100%	4 100%	4 100%	45 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	4 100%	4 100%	4 100%	4 100%	4 100%	4 100%	5 100%	4 100%	4 100%	4 100%	4 100%	45 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	1 25%	0 0%	0 0%	0 0%	0 0%	0 0%	1 2.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	4 100%	4 100%	4 100%	4 100%	4 100%	3 75%	5 100%	4 100%	4 100%	4 100%	4 100%	44 97.8%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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.

Outcome Measure Data

Analysis Population Description
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/Group Title	Verapamil + R1 (T1)	Cocktail (R1)
Arm/Group Description	Participants were administered a single dose of 120 mg Verapamil orally with 240 mL of water at 1 h prior to the R1 which is administered with 280 mL of water in trial part 1.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	12	12
Digoxin	13.71 (1.10)	13.61 (1.10)
Furosemide	165.80 (1.06)	176.85 (1.06)
Metformin	1126.22 (1.05)	1357.34 (1.05)
Rosuvastatin	98.98 (1.11)	87.29 (1.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	100.70
	Confidence Interval	(2-Sided) 90% 88.84 to 114.15
	Parameter Dispersion	Type: Standard Error of the Mean Value: 17.9
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Digoxin, Analysis of variance (ANOVA) model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	93.76
	Confidence Interval	(2-Sided) 90% 86.12 to 102.06
	Parameter Dispersion	Type: Standard Error of the Mean Value: 12.1
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	82.97
	Confidence Interval	(2-Sided) 90% 76.96 to 89.46
	Parameter Dispersion	Type: Standard Error of the Mean Value: 10.7
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	113.40
	Confidence Interval	(2-Sided) 90% 97.62 to 131.72
	Parameter Dispersion	Type: Standard Error of the Mean Value: 21.5
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

2. Primary Outcome

Title	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)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Rifampin + R1 (T2)	Cocktail (R1)
Arm/Group Description	Participants were administered a single dose of 600 mg Rifampin film-coated tablet orally with 280 mL of water together with Cocktail in trial part 1.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	12	12
Digoxin	17.89 (1.10)	13.61 (1.10)
Furosemide	211.82 (1.06)	176.85 (1.06)
Metformin	1473.38 (1.05)	1357.34 (1.05)
Rosuvastatin	303.81 (1.11)	87.29 (1.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	131.41
	Confidence Interval	(2-Sided) 90% 115.93 to 148.97
	Parameter Dispersion	Type: Standard Error of the Mean Value: 17.9
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Digoxin, Analysis of variance (ANOVA) model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	119.78
	Confidence Interval	(2-Sided) 90% 110.03 to 130.39
	Parameter Dispersion	Type: Standard Error of the Mean Value: 12.1
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	108.55
	Confidence Interval	(2-Sided) 90% 100.68 to 117.03
	Parameter Dispersion	Type: Standard Error of the Mean Value: 10.7
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	348.06
	Confidence Interval	(2-Sided) 90% 299.64 to 404.31
	Parameter Dispersion	Type: Standard Error of the Mean Value: 21.5
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

3. Primary Outcome

Title	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)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Cimetidine + R1 (T3)	Cocktail (R1)
Arm/Group Description	Participants were administered 400 mg Cimetidine 1 tablet orally at 1 h prior to cocktail and at 4 h, 8 h, 12 h, 24 h (Day 2) and 36 h after cocktail (Day 2). All doses of Cimetidine administered with 240 mL water and dose of Cocktail with 280 mL of water in trial part 2.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	15	13
Digoxin	19.03 (1.07)	15.15 (1.07)
Furosemide	196.39 (1.05)	194.05 (1.05)
Metformin	2006.60 (1.06)	1532.41 (1.07)
Rosuvastatin	139.54 (1.13)	129.90 (1.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	125.61
	Confidence Interval	(2-Sided) 90% 113.99 to 138.43
	Parameter Dispersion	Type: Standard Error of the Mean Value: 13.2
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T3 vs. R1.

Other Statistical Analysis		Digoxin, Analysis of variance (ANOVA) model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	101.21
	Confidence Interval	(2-Sided) 90% 94.59 to 108.30
	Parameter Dispersion	Type: Standard Error of the Mean Value: 9.2
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T3 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	130.94
	Confidence Interval	(2-Sided) 90% 119.82 to 143.10
	Parameter Dispersion	Type: Standard Error of the Mean Value: 13.6
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T3 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	107.42
	Confidence Interval	(2-Sided) 90% 97.57 to 118.27
	Parameter Dispersion	Type: Standard Error of the Mean Value: 12.9
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T3 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

4. Primary Outcome

Title	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)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Probenecid + R1 (T4)	Cocktail (R1)
Arm/Group Description	Participants were administered 2 tablets of 500 mg Probenecid (2*500 mg) orally 13 h prior and again 1 h prior to the administration of R1 on day 1. All doses of Cimetidine administered with 240 mL water and dose of R1 which is administered with 280 mL of water in trial part 3.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	15	16
Digoxin	14.44 (1.08)	13.52 (1.08)
Furosemide	483.38 (1.08)	177.96 (1.07)
Metformin	1331.83 (1.08)	1321.20 (1.08)
Rosuvastatin	238.16 (1.10)	106.69 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	106.78
	Confidence Interval	(2-Sided) 90% 96.51 to 118.15
	Parameter Dispersion	Type: Standard Error of the Mean Value: 15.5
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Digoxin, Analysis of variance (ANOVA) model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	271.63
	Confidence Interval	(2-Sided) 90% 246.74 to 299.03
	Parameter Dispersion	Type: Standard Error of the Mean Value: 15.9
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	100.80
	Confidence Interval	(2-Sided) 90% 94.62 to 107.39
	Parameter Dispersion	Type: Standard Error of the Mean Value: 9.6
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	223.24
	Confidence Interval	(2-Sided) 90% 203.79 to 244.55
	Parameter Dispersion	Type: Standard Error of the Mean Value: 13.9
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

5. Primary Outcome

Title	Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Verapamil + R1 (T1)	Cocktail (R1)
Arm/Group Description	Participants were administered a single dose of 120 mg Verapamil orally with 240 mL of water at 1 h prior to the R1 which is administered with 280 mL of water in trial part 1.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	12	12
Digoxin	1.42 (1.09)	1.17 (1.09)
Furosemide	84.32 (1.06)	88.59 (1.06)
Metformin	179.45 (1.04)	223.78 (1.04)
Rosuvastatin	7.90 (1.14)	6.84 (1.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	121.64
	Confidence Interval	(2-Sided) 90% 100.43 to 147.33
	Parameter Dispersion	Type: Standard Error of the Mean Value: 27.7
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Digoxin, Analysis of variance (ANOVA) model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	95.18
	Confidence Interval	(2-Sided) 90% 83.03 to 109.11
	Parameter Dispersion	Type: Standard Error of the Mean Value: 19.6
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	80.19
	Confidence Interval	(2-Sided) 90% 73.01 to 88.08
	Parameter Dispersion	Type: Standard Error of the Mean Value: 13.4
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	115.39
	Confidence Interval	(2-Sided) 90% 93.80 to 141.94
	Parameter Dispersion	Type: Standard Error of the Mean Value: 30.1
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

6. Primary Outcome

Title	Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Rifampin + R1 (T2)	Cocktail (R1)
Arm/Group Description	Participants were administered a single dose of 600 mg Rifampin film-coated tablet orally with 280 mL of water together with Cocktail in trial part 1.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	12	12
Digoxin	2.55 (1.09)	1.17 (1.09)
Furosemide	119.66 (1.06)	88.59 (1.06)
Metformin	251.32 (1.04)	223.78 (1.04)
Rosuvastatin	77.00 (1.14)	6.84 (1.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	218.26
	Confidence Interval	(2-Sided) 90% 180.19 to 264.36
	Parameter Dispersion	Type: Standard Error of the Mean Value: 27.7
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Digoxin, Analysis of variance (ANOVA) model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	135.07
	Confidence Interval	(2-Sided) 90% 117.83 to 154.84
	Parameter Dispersion	Type: Standard Error of the Mean Value: 19.6
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	112.31
	Confidence Interval	(2-Sided) 90% 102.26 to 123.35
	Parameter Dispersion	Type: Standard Error of the Mean Value: 13.4
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	1125.10
	Confidence Interval	(2-Sided) 90% 914.63 to 1384.00
	Parameter Dispersion	Type: Standard Error of the Mean Value: 30.1
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

7. Primary Outcome

Title	Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Cimetidine + R1 (T3)	Cocktail (R1)
Arm/Group Description	Participants were administered 400 mg Cimetidine 1 tablet orally at 1 h prior to cocktail and at 4 h, 8 h, 12 h, 24 h (Day 2) and 36 h after cocktail (Day 2). All doses of Cimetidine administered with 240 mL water and dose of Cocktail with 280 mL of water in trial part 2.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	15	13
Digoxin	1.65 (1.07)	1.35 (1.08)
Furosemide	97.69 (1.08)	93.23 (1.08)
Metformin	316.83 (1.07)	258.33 (1.08)
Rosuvastatin	13.21 (1.15)	11.30 (1.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	218.26
	Confidence Interval	(2-Sided) 90% 180.19 to 264.36
	Parameter Dispersion	Type: Standard Error of the Mean Value: 27.7
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T3 vs. R1.

Other Statistical Analysis		Digoxin, Analysis of variance (ANOVA) model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	104.78
	Confidence Interval	(2-Sided) 90% 89.97 to 122.03
	Parameter Dispersion	Type: Standard Error of the Mean Value: 21.0
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T3 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	122.65
	Confidence Interval	(2-Sided) 90% 107.68 to 139.69
	Parameter Dispersion	Type: Standard Error of the Mean Value: 20.1
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	116.88
	Confidence Interval	(2-Sided) 90% 105.07 to 130.03
	Parameter Dispersion	Type: Standard Error of the Mean Value: 14.4
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T3 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

8. Primary Outcome

Title	Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Probenecid + R1 (T4)	Cocktail (R1)
Arm/Group Description	Participants were administered 2 tablets of 500 mg Probenecid (2*500 mg) orally 13 h prior and again 1 h prior to the administration of R1 on day 1. All doses of Cimetidine administered with 240 mL water and dose of R1 which is administered with 280 mL of water in trial part 3.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	15	16
Digoxin	1.13 (1.07)	1.30 (1.07)
Furosemide	110.64 (1.07)	90.00 (1.07)
Metformin	246.78 (1.12)	243.49 (1.12)
Rosuvastatin	43.29 (1.11)	10.11 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted geometric mean (gMean) ratio
	Estimated Value	87.07
	Confidence Interval	(2-Sided) 90% 76.08 to 99.64
	Parameter Dispersion	Type: Standard Error of the Mean Value: 20.9
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Digoxin, Analysis of variance (ANOVA) model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	122.94
	Confidence Interval	(2-Sided) 90% 110.25 to 137.09
	Parameter Dispersion	Type: Standard Error of the Mean Value: 18.0
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	101.35
	Confidence Interval	(2-Sided) 90% 93.65 to 109.70
	Parameter Dispersion	Type: Standard Error of the Mean Value: 12.0
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	428.23
	Confidence Interval	(2-Sided) 90% 359.78 to 509.70
	Parameter Dispersion	Type: Standard Error of the Mean Value: 26.8
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

9. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T1 vs. R1)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Verapamil + R1 (T1)	Cocktail (R1)
Arm/Group Description	Participants were administered a single dose of 120 mg Verapamil orally with 240 mL of water at 1 h prior to the R1 which is administered with 280 mL of water in trial part 1.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	12	12
Furosemide	176.44 (1.06)	191.29 (1.06)
Metformin	1147.23 (1.05)	1365.85 (1.05)
Rosuvastatin	116.80 (1.10)	94.14 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	92.24
	Confidence Interval	(2-Sided) 90% 85.28 to 99.76
	Parameter Dispersion	Type: Standard Error of the Mean Value: 11.2
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	83.99
	Confidence Interval	(2-Sided) 90% 78.32 to 90.08
	Parameter Dispersion	Type: Standard Error of the Mean Value: 10.0
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	124.06
	Confidence Interval	(2-Sided) 90% 105.11 to 146.43
	Parameter Dispersion	Type: Standard Error of the Mean Value: 23.9
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T1 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

10. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T2 vs. R1)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Rifampin + R1 (T2)	Cocktail (R1)
Arm/Group Description	Participants were administered a single dose of 600 mg Rifampin film-coated tablet orally with 280 mL of water together with Cocktail in trial part 1.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	12	12
Furosemide	215.63 (1.06)	191.29 (1.06)
Metformin	1482.76 (1.05)	1365.85 (1.05)
Rosuvastatin	320.72 (1.10)	94.14 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	112.73
	Confidence Interval	(2-Sided) 90% 104.23 to 121.92
	Parameter Dispersion	Type: Standard Error of the Mean Value: 11.2
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	108.56
	Confidence Interval	(2-Sided) 90% 101.22 to 116.43
	Parameter Dispersion	Type: Standard Error of the Mean Value: 10.0
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	340.67
	Confidence Interval	(2-Sided) 90% 288.63 to 402.10
	Parameter Dispersion	Type: Standard Error of the Mean Value: 23.9
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T2 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

11. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T3 vs. R1)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Cimetidine + R1 (T3)	Cocktail (R1)
Arm/Group Description	Participants were administered 400 mg Cimetidine 1 tablet orally at 1 h prior to cocktail and at 4 h, 8 h, 12 h, 24 h (Day 2) and 36 h after cocktail (Day 2). All doses of Cimetidine administered with 240 mL water and dose of Cocktail with 280 mL of water in trial part 2.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	15	13
Furosemide	202.17 (1.04)	200.61 (1.05)
Metformin	2023.33 (1.06)	1540.21 (1.07)
Rosuvastatin	148.32 (1.13)	139.21 (1.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	100.78
	Confidence Interval	(2-Sided) 90% 93.59 to 108.51
	Parameter Dispersion	Type: Standard Error of the Mean Value: 10.0
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T3 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	131.37
	Confidence Interval	(2-Sided) 90% 120.37 to 143.37
	Parameter Dispersion	Type: Standard Error of the Mean Value: 13.4
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	106.55
	Confidence Interval	(2-Sided) 90% 96.87 to 117.19
	Parameter Dispersion	Type: Standard Error of the Mean Value: 12.8
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T3 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

12. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) (T4 vs. R1)
Description	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.

Outcome Measure Data

Analysis Population Description
PKS

Arm/Group Title	Probenecid + R1 (T4)	Cocktail (R1)
Arm/Group Description	Participants were administered 2 tablets of 500 mg Probenecid (2*500 mg) orally 13 h prior and again 1 h prior to the administration of R1 on day 1. All doses of Cimetidine administered with 240 mL water and dose of R1 which is administered with 280 mL of water in trial part 3.	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.
Measure Participants	15	16
Furosemide	489.28 (1.07)	188.11 (1.07)
Metformin	1346.62 (1.08)	1330.47 (1.07)
Rosuvastatin	244.94 (1.10)	113.78 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean ratio
	Estimated Value	260.11
	Confidence Interval	(2-Sided) 90% 237.96 to 284.32
	Parameter Dispersion	Type: Standard Error of the Mean Value: 14.7
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Furosemide, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	101.21
	Confidence Interval	(2-Sided) 90% 95.15 to 107.66
	Parameter Dispersion	Type: Standard Error of the Mean Value: 9.4
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Metformin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Verapamil + R1 (T1), Cocktail (R1)
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Adjusted gMean Ratio
	Estimated Value	215.28
	Confidence Interval	(2-Sided) 90% 197.53 to 234.63
	Parameter Dispersion	Type: Standard Error of the Mean Value: 13.1
	Estimation Comments	Standard Error of the mean is actually intra individual geometric coefficient of variation (gCV). Adjusted gMean ratio is given for T4 vs. R1.

Other Statistical Analysis		Rosuvastatin, ANOVA model on the logarithmic scale includes effects accounting for the following sources of variation: 'sequence', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.

Adverse Events

	Cocktail (R1)		Verapamil + R1 (T1)		Rifampin + R1 (T2)		Metformin (R2)		Cimetidine + R1 (T3)		Cimetidine + R2 (T5)		Furosemide (R3)		Probenecid + R1 (T4)		Probenecid + R3 (T6)
Time Frame	From first drug administration until 7 days thereafter in each treatment period, up to 22 days for part 1 and 27 days for part 2 and 3.
Adverse Event Reporting Description	Treatment emergent adverse events (AE's) are presented are on-treatment and treated set (TS) was used for AE reporting.

Arm/Group Title	Cocktail (R1)		Verapamil + R1 (T1)		Rifampin + R1 (T2)		Metformin (R2)		Cimetidine + R1 (T3)		Cimetidine + R2 (T5)		Furosemide (R3)		Probenecid + R1 (T4)		Probenecid + R3 (T6)
Arm/Group Description	Participants were administered a single dose of Cocktail (reference treatment 1, R1) with 280 mL of water. 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 trial part 1, 2 and 3.		Participants were administered a single dose of 120 mg Verapamil orally with 240 mL of water at 1 h prior to the R1 which is administered with 280 mL of water 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 trial part 1.		Participants were administered a single therapeutic dose of 500 mg Metformin oral solution with 280 mL of water 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). All doses of Cimetidine administered with 240 mL water and dose of R1 which is administered with 280 mL of water 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 therapeutic dose of 500 mg Metformin (Day 2) in trial part 2.		Participants were administered orally a single therapeutic dose of 40 mg Furosemide oral solution with 280 mL of water in trial part 3.		Participants were administered 2 tablets of 500 mg Probenecid (2*500 mg) orally 13 h prior and again 1 h prior to the administration of R1 on day 1. All doses of Cimetidine administered with 240 mL water and dose of R1 which is administered with 280 mL of water 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 trial part 3.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Serious Adverse Events
	Cocktail (R1)		Verapamil + R1 (T1)		Rifampin + R1 (T2)		Metformin (R2)		Cimetidine + R1 (T3)		Cimetidine + R2 (T5)		Furosemide (R3)		Probenecid + R1 (T4)		Probenecid + R3 (T6)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Cocktail (R1)		Verapamil + R1 (T1)		Rifampin + R1 (T2)		Metformin (R2)		Cimetidine + R1 (T3)		Cimetidine + R2 (T5)		Furosemide (R3)		Probenecid + R1 (T4)		Probenecid + R3 (T6)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/42 (11.9%)		1/12 (8.3%)		2/12 (16.7%)		7/16 (43.8%)		7/17 (41.2%)		7/17 (41.2%)		4/16 (25%)		4/16 (25%)		3/15 (20%)
Cardiac disorders
Palpitations	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		1/17 (5.9%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Ear and labyrinth disorders
Vertigo	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		1/17 (5.9%)		1/17 (5.9%)		0/16 (0%)		0/16 (0%)		1/15 (6.7%)
Eye disorders
Dry eye	0/42 (0%)		0/12 (0%)		0/12 (0%)		1/16 (6.3%)		0/17 (0%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Gastrointestinal disorders
Abdominal distension	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		1/17 (5.9%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Abdominal pain upper	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		1/17 (5.9%)		1/17 (5.9%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Diarrhoea	1/42 (2.4%)		0/12 (0%)		0/12 (0%)		1/16 (6.3%)		1/17 (5.9%)		1/17 (5.9%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Dry mouth	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		1/17 (5.9%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Dysphagia	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		1/17 (5.9%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Flatulence	1/42 (2.4%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		1/17 (5.9%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Nausea	0/42 (0%)		0/12 (0%)		0/12 (0%)		1/16 (6.3%)		1/17 (5.9%)		2/17 (11.8%)		0/16 (0%)		1/16 (6.3%)		1/15 (6.7%)
Vomiting	1/42 (2.4%)		0/12 (0%)		1/12 (8.3%)		0/16 (0%)		0/17 (0%)		1/17 (5.9%)		1/16 (6.3%)		0/16 (0%)		0/15 (0%)
General disorders
Chest pain	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		1/17 (5.9%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Influenza like illness	0/42 (0%)		0/12 (0%)		0/12 (0%)		1/16 (6.3%)		0/17 (0%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Malaise	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		1/15 (6.7%)
Immune system disorders
Hypersensitivity	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		0/17 (0%)		0/16 (0%)		1/16 (6.3%)		0/15 (0%)
Infections and infestations
Nasopharyngitis	1/42 (2.4%)		1/12 (8.3%)		1/12 (8.3%)		1/16 (6.3%)		0/17 (0%)		1/17 (5.9%)		1/16 (6.3%)		1/16 (6.3%)		0/15 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		0/17 (0%)		1/16 (6.3%)		0/16 (0%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		0/17 (0%)		1/16 (6.3%)		0/16 (0%)		0/15 (0%)
Nervous system disorders
Dizziness	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		0/17 (0%)		0/16 (0%)		1/16 (6.3%)		0/15 (0%)
Headache	2/42 (4.8%)		0/12 (0%)		1/12 (8.3%)		4/16 (25%)		3/17 (17.6%)		2/17 (11.8%)		2/16 (12.5%)		0/16 (0%)		1/15 (6.7%)
Orthostatic intolerance	0/42 (0%)		0/12 (0%)		1/12 (8.3%)		0/16 (0%)		0/17 (0%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Psychiatric disorders
Conversion disorder	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		1/17 (5.9%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Restlessness	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		1/17 (5.9%)		0/17 (0%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		1/17 (5.9%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Oropharyngeal pain	0/42 (0%)		0/12 (0%)		0/12 (0%)		1/16 (6.3%)		0/17 (0%)		1/17 (5.9%)		0/16 (0%)		0/16 (0%)		0/15 (0%)
Skin and subcutaneous tissue disorders
Erythema	0/42 (0%)		0/12 (0%)		0/12 (0%)		0/16 (0%)		0/17 (0%)		0/17 (0%)		0/16 (0%)		1/16 (6.3%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.

Results Point of Contact

Name/Title	Boehringer Ingelheim, Call Centre
Organization	Boehringer Ingelheim
Phone	1-800-243-0127
Email	clintriage.rdg@boehringer-ingelheim.com

Responsible Party:

Boehringer Ingelheim

ClinicalTrials.gov Identifier:

NCT03307252

Other Study ID Numbers:

0352-2100
2017-001549-29

First Posted:

Oct 11, 2017

Last Update Posted:

Jul 12, 2019

Last Verified:

Apr 1, 2019