Transporter Cocktail Mutual Interaction

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02854527
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 5
• Actual Duration (Months): 2.9
• Patients Per Site Per Month: 10.3

Study Details

Study Description

Brief Summary

Main objective is to investigate mutual pharmacokinetic drug-drug interactions of digoxin, furosemide, metformin, and rosuvastatin when given all together as a cocktail

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Digoxin; Drug: Furosemide; Drug: Metformin; Drug: Rosuvastatin; Drug: Digoxin; Drug: Furosemide; Drug: Metformin hydrochloride; Drug: Rosuvastatin	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Investigation of Mutual Pharmacokinetic Interactions of Digoxin, Furosemide, Metformin, and Rosuvastatin Given All Together as a Probe Cocktail for Key Drug Transporters (an Open-label, Randomised, Single-dose, Five-way Crossover Study)
• Actual Study Start Date: Aug 22, 2016
• Actual Primary Completion Date: Nov 11, 2016
• Actual Study Completion Date: Nov 19, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: R1 (Reference 1) Digoxin 1 tablet (0.25 mg) digoxin as single dose	Drug: Digoxin; single dose
Experimental: R2 Furosemide 0.1 mL (1 mg) furosemide oral solution as single dose	Drug: Furosemide; single dose
Experimental: R3 Metformin hydrochloride 0.1 mL (10 mg) metformin oral solution as single dose	Drug: Metformin; single dose
Experimental: R4 Rosuvastatin 1 tablet (10 mg) rosuvastatin as single dose	Drug: Rosuvastatin; single dose
Experimental: T (Test) 1 tablet (0.25 mg) digoxin, 0.1 mL (1 mg) furosemide oral solution, 0.1 mL (10 mg) metformin oral solution, and 1 tablet (10 mg) rosuvastatin, all together as a single dose ('cocktail')	Drug: Digoxin; 0.25 mg digoxin as single dose (all 4 drugs given together as a cocktail at the same time point); Drug: Furosemide; 1 mg furosemide as single dose (all 4 drugs given together as a cocktail at the same time point); Drug: Metformin hydrochloride; 10 mg metformin hydrochloride as single dose (all 4 drugs given together as a cocktail at the same time point); Drug: Rosuvastatin; 10 mg rosuvastatin as single dose (all 4 drugs given together as a cocktail at the same time point)

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve of Digoxin From 0 to Last Quantifiable Data Point (AUC 0-tz) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration]

   Area under the concentration-time curve of digoxin in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error. CI - confidence interval, gMean - geometric mean.

2. Maximum Concentration of Digoxin (Cmax) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration]

   This outcome measure presents the maximum measured concentration of digoxin in plasma (Cmax). Standard error presented is actually geometric standard error.

3. Area Under the Curve of Furosemide From 0 to Last Quantifiable Data Point (AUC 0-tz) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 24:00 after drug administration]

   Area under the concentration-time curve of furosemide in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error.

4. Maximum Concentration of Furosemide (Cmax) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 24:00 after drug administration]

   This outcome measure presents the maximum measured concentration of furosemide in plasma (Cmax). Standard error presented is actually geometric standard error.

5. Area Under the Curve of Metformin From 0 to Last Quantifiable Data Point (AUC 0-tz) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00 and 48:00 after drug administration]

   Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error.

6. Maximum Concentration of Metformin (Cmax) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00 and 48:00 after drug administration]

   This outcome measure presents the maximum measured concentration of metformin in plasma (Cmax). Standard error presented is actually geometric standard error.

7. Area Under the Curve of Rosuvastatin From 0 to Last Quantifiable Data Point (AUC 0-tz) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration]

   Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error.

8. Maximum Concentration of Rosuvastatin (Cmax) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration]

   This outcome measure presents the maximum measured concentration of rosuvastatin in plasma (Cmax). Standard error presented is actually geometric standard error.

Secondary Outcome Measures

1. Area Under the Curve of Digoxin From 0 Extrapolated to Infinity (AUC 0-∞) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration]

   Area under the concentration-time curve of digoxin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.

2. Area Under the Curve of Furosemide From 0 Extrapolated to Infinity (AUC 0-∞) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 24:00 after drug administration]

   Area under the concentration-time curve of furosemide in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.

3. Area Under the Curve of Metformin From 0 Extrapolated to Infinity (AUC 0-∞) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00 and 48:00 after drug administration]

   Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.

4. Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC 0-∞) [Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration]

   Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.

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 and local legislation

Exclusion criteria:

• Any finding in the medical examination (including BP, PR or 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 that might reasonably influence the results of the trial (incl. QT/QTc interval prolongation (corrected Q-T interval)

• 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 30 g per day)

• 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

In addition, the following trial-specific exclusion criteria apply:

• Hypokalemia, hypomagnesemia, or hypercalcemia

• PQ ( (time between the onset of the P wave (atrial activity) and the QRS complex (ventricular activity)) interval greater than 220 ms in the ECG at screening

• Myopathy

• Hereditary galactose or fructose intolerance, lactase deficiency, or glucose-galactose malabsorption

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boehringer Ingelheim Pharma GmbH & Co KG	Biberach		Germany	88397

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Synopsis Link

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02854527
• Other Study ID Numbers: 352.2096; 2016-001893-14
• First Posted: Aug 3, 2016
• Last Update Posted: Aug 6, 2018
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Metformin; Digoxin; Furosemide; Rosuvastatin Calcium

Study Results

Participant Flow

Pre-assignment Detail	This is an open-label, randomised, single-dose, five-way, ten-sequence crossover study. Four drugs (Digoxin (R1), Furosemide, (R2), Metformin hydrochloride (R3), Rosuvastatin (R4)) were given as monotherapy and one as a combination of all four drugs together as test cocktail (T) in pre-defined sequences.

Arm/Group Title	ABECD (R1->R2->T->R3->R4)	AEBDC (R1->T->R2->R4->R3)	BACED (R2->R1->R3->T->R4)	BCADE (R2->R3->R1->R4->T)	CBDAE (R3->R2->R4->R1->T)	CDBEA (R3->R4->R2->T->R1)	DCEBA (R4->R3->T->R2->R1)	DECAB (R4->T->R3->R1->R2)	EADBC (T->R1->R4->R2->R3)	EDACB (T->R4->R1->R3->R2)
Arm/Group Description	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (reference 1 or R1). Second, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Third, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Fourth, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Fifth, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (reference 1 or R1). Second, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Third, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Fourth, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Fifth, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (reference 2 or R2). Second, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Third, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Fourth, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Fifth, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Second, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Third, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Fourth, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Fifth, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Second, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Third, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Fourth, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Fifth, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Second, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Third, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Fourth, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Fifth, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Second, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Third, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Fourth, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Fifth, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Second, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Third, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Fourth, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Fifth, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Second, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Third, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Fourth, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Fifth, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Second, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Third, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Fourth, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Fifth, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Period Title: Overall Study
STARTED	3	3	3	3	3	3	3	3	3	3
Received R1	3	3	3	2	2	3	3	3	3	3
Received R2	3	3	3	3	3	3	3	3	3	3
Received R3	3	3	3	2	3	3	3	3	3	3
Received R4	3	3	3	2	3	3	3	3	3	3
Received T	3	3	3	2	2	3	3	3	3	3
COMPLETED	3	3	3	2	2	3	3	3	3	3
NOT COMPLETED	0	0	0	1	1	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	ABECD (R1->R2->T->R3->R4)	AEBDC (R1->T->R2->R4->R3)	BACED (R2->R1->R3->T->R4)	BCADE (R2->R3->R1->R4->T)	CBDAE (R3->R2->R4->R1->T)	CDBEA (R3->R4->R2->T->R1)	DCEBA (R4->R3->T->R2->R1)	DECAB (R4->T->R3->R1->R2)	EADBC (T->R1->R4->R2->R3)	EDACB (T->R4->R1->R3->R2)	Total
Arm/Group Description	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (reference 1 or R1). Second, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Third, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Fourth, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Fifth, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (reference 1 or R1). Second, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Third, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Fourth, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Fifth, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (reference 2 or R2). Second, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Third, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Fourth, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Fifth, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Second, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Third, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Fourth, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Fifth, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Second, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Third, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Fourth, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Fifth, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Second, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Third, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Fourth, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Fifth, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Second, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Third, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Fourth, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Fifth, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Second, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Third, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Fourth, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Fifth, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Second, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Third, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Fourth, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). Fifth, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects in this sequence were administered five different treatments in a sequence with a washout period of at least 10 days between each drug administration of adjacent treatment periods. First, they were administered a single dose of test cocktail (T) comprised of 0.25 mg of Digoxin, 0.1 mL (1 mg) of Furosemide, 0.1 mL (10 mg) of Metformin hydrochloride and 10 mg of Rosuvastatin. Second, they were administered a single dose of 10 mg film-coated tablet of Rosuvastatin (R4). Third, they were administered a single dose of 0.25 milligram (mg) tablet of Digoxin (R1). Fourth, they were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride (R3). Fifth, they were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide (R2). All drugs were administered orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Total of all reporting groups
Overall Participants	3	3	3	3	3	3	3	3	3	3	30
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	26.7 (2.5)	28.7 (8.1)	41.3 (15.8)	42.0 (5.3)	32.3 (9.0)	45.7 (7.2)	30.3 (6.4)	33.0 (9.6)	40.3 (7.5)	34.3 (7.2)	35.5 (9.4)
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%
Male	3 100%	3 100%	3 100%	3 100%	3 100%	3 100%	3 100%	3 100%	3 100%	3 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve of Digoxin From 0 to Last Quantifiable Data Point (AUC 0-tz)
Description	Area under the concentration-time curve of digoxin in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error. CI - confidence interval, gMean - geometric mean.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis set (PKS) included all randomized subjects who were documented to have taken at least 1 dose of study drug and who have provided at least 1 primary or secondary PK endpoint that was not excluded from analysis due to non-evaluability or protocol violation relevant for the evaluation of the pharmacokinetics.

Arm/Group Title	Test Cocktail (T)	Digoxin (R1)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 0.25 milligram (mg) tablet of Digoxin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	28	28
Geometric Mean (Standard Error) [nanomole hour per liter (nmol·h/L)]	11.549 (1.053)	11.981 (1.053)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the first primary outcome measure of treatment R1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R1) (%)
	Estimated Value	96.39
	Confidence Interval	(2-Sided) 90%; 88.22 to 105.33
	Parameter Dispersion	Type: Standard Deviation; Value: 19.4
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R1 were back transformed to original scale to get adjusted gMean ratio (T/R1) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

2. Primary Outcome

Title	Maximum Concentration of Digoxin (Cmax)
Description	This outcome measure presents the maximum measured concentration of digoxin in plasma (Cmax). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Digoxin (R1)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 0.25 milligram (mg) tablet of Digoxin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	28	28
Geometric Mean (Standard Error) [nanomole per liter (nmol/L)]	1.262 (1.047)	1.355 (1.047)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the second primary outcome measure of treatment R1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R1) (%)
	Estimated Value	93.17
	Confidence Interval	(2-Sided) 90%; 83.49 to 103.97
	Parameter Dispersion	Type: Standard Deviation; Value: 24.1
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R1 were back transformed to original scale to get adjusted gMean ratio (T/R1) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

3. Primary Outcome

Title	Area Under the Curve of Furosemide From 0 to Last Quantifiable Data Point (AUC 0-tz)
Description	Area under the concentration-time curve of furosemide in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 24:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Furosemide (R2)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	28	30
Geometric Mean (Standard Error) [nmol·h/L]	163.614 (1.039)	159.434 (1.038)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the first primary outcome measure of treatment R2.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R2) (%)
	Estimated Value	102.62
	Confidence Interval	(2-Sided) 90%; 93.82 to 112.25
	Parameter Dispersion	Type: Standard Deviation; Value: 20.4
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R2 were back transformed to original scale to get adjusted gMean ratio (T/R2) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

4. Primary Outcome

Title	Maximum Concentration of Furosemide (Cmax)
Description	This outcome measure presents the maximum measured concentration of furosemide in plasma (Cmax). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 24:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Furosemide (R2)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	28	30
Geometric Mean (Standard Error) [nmol/L]	86.275 (1.046)	82.990 (1.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the second primary outcome measure of treatment R2.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R2) (%)
	Estimated Value	103.96
	Confidence Interval	(2-Sided) 90%; 93.60 to 115.46
	Parameter Dispersion	Type: Standard Deviation; Value: 24.0
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R2 were back transformed to original scale to get adjusted gMean ratio (T/R2) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

5. Primary Outcome

Title	Area Under the Curve of Metformin From 0 to Last Quantifiable Data Point (AUC 0-tz)
Description	Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00 and 48:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Metformin Hydrochloride (R3)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	28	29
Geometric Mean (Standard Error) [nmol·h/L]	1283.797 (1.034)	1316.790 (1.033)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the first primary outcome measure of treatment R3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R3) (%)
	Estimated Value	97.49
	Confidence Interval	(2-Sided) 90%; 93.54 to 101.61
	Parameter Dispersion	Type: Standard Deviation; Value: 9.0
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R3 were back transformed to original scale to get adjusted gMean ratio (T/R3) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

6. Primary Outcome

Title	Maximum Concentration of Metformin (Cmax)
Description	This outcome measure presents the maximum measured concentration of metformin in plasma (Cmax). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00 and 48:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Metformin Hydrochloride (R3)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	28	29
Geometric Mean (Standard Error) [nmol/L]	225.156 (1.045)	229.171 (1.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the second primary outcome measure of treatment R3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R3) (%)
	Estimated Value	98.25
	Confidence Interval	(2-Sided) 90%; 91.85 to 105.09
	Parameter Dispersion	Type: Standard Deviation; Value: 14.7
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R3 were back transformed to original scale to get adjusted gMean ratio (T/R3) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

7. Primary Outcome

Title	Area Under the Curve of Rosuvastatin From 0 to Last Quantifiable Data Point (AUC 0-tz)
Description	Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 to the last quantifiable data point (AUC 0-tz). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Rosuvastatin (R4)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	28	29
Geometric Mean (Standard Error) [nmol·h/L]	81.925 (1.070)	78.016 (1.069)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the first primary outcome measure of treatment R4.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R4) (%)
	Estimated Value	105.01
	Confidence Interval	(2-Sided) 90%; 96.39 to 114.40
	Parameter Dispersion	Type: Standard Deviation; Value: 18.8
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R4 were back transformed to original scale to get adjusted gMean ratio (T/R4) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

8. Primary Outcome

Title	Maximum Concentration of Rosuvastatin (Cmax)
Description	This outcome measure presents the maximum measured concentration of rosuvastatin in plasma (Cmax). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Rosuvastatin (R4)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	28	29
Geometric Mean (Standard Error) [nmol/L]	8.135 (1.074)	7.801 (1.073)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the second primary outcome measure of treatment R4.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R4) (%)
	Estimated Value	104.28
	Confidence Interval	(2-Sided) 90%; 94.95 to 114.53
	Parameter Dispersion	Type: Standard Deviation; Value: 20.6
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R4 were back transformed to original scale to get adjusted gMean ratio (T/R4) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

9. Secondary Outcome

Title	Area Under the Curve of Digoxin From 0 Extrapolated to Infinity (AUC 0-∞)
Description	Area under the concentration-time curve of digoxin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Digoxin (R1)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 0.25 milligram (mg) tablet of Digoxin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	27	28
Geometric Mean (Standard Error) [nmol·h/L]	17.668 (1.039)	18.303 (1.039)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the secondary outcome measure of treatment R1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R1) (%)
	Estimated Value	96.53
	Confidence Interval	(2-Sided) 90%; 92.08 to 101.20
	Parameter Dispersion	Type: Standard Deviation; Value: 10.1
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R1 were back transformed to original scale to get adjusted gMean ratio (T/R1) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

10. Secondary Outcome

Title	Area Under the Curve of Furosemide From 0 Extrapolated to Infinity (AUC 0-∞)
Description	Area under the concentration-time curve of furosemide in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 24:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Furosemide (R2)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	20	20
Geometric Mean (Standard Error) [nmol·h/L]	156.382 (1.049)	160.551 (1.052)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the secondary outcome measure of treatment R2.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R2) (%)
	Estimated Value	97.40
	Confidence Interval	(2-Sided) 90%; 90.87 to 104.41
	Parameter Dispersion	Type: Standard Deviation; Value: 9.6
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R2 were back transformed to original scale to get adjusted gMean ratio (T/R2) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

11. Secondary Outcome

Title	Area Under the Curve of Metformin From 0 Extrapolated to Infinity (AUC 0-∞)
Description	Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00 and 48:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Metformin Hydrochloride (R3)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	28	29
Geometric Mean (Standard Error) [nmol·h/L]	1290.928 (1.033)	1324.078 (1.033)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the secondary outcome measure of treatment R3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R3) (%)
	Estimated Value	97.50
	Confidence Interval	(2-Sided) 90%; 93.58 to 101.58
	Parameter Dispersion	Type: Standard Deviation; Value: 8.9
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R3 were back transformed to original scale to get adjusted gMean ratio (T/R3) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

12. Secondary Outcome

Title	Area Under the Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC 0-∞)
Description	Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). Standard error presented is actually geometric standard error.
Time Frame	Blood sampling at 2:00 (hour: minute) before drug administration, 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 36:00, 48:00, 72:00 and 96:00 after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Test Cocktail (T)	Rosuvastatin (R4)
Arm/Group Description	Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.	Subjects were administered a single dose of 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
Measure Participants	22	25
Geometric Mean (Standard Error) [nmol·h/L]	97.385 (1.072)	90.479 (1.069)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Test Cocktail (T), Digoxin (R1)
	Comments	This statistical analysis assess the effect of the other cocktail compounds in treatment T on the secondary outcome measure of treatment R4.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Geometric mean ratio (T/R4) (%)
	Estimated Value	107.63
	Confidence Interval	(2-Sided) 90%; 97.04 to 119.39
	Parameter Dispersion	Type: Standard Deviation; Value: 19.4
	Estimation Comments	Least square estimates of log-transformed PK endpoint for T and R4 were back transformed to original scale to get adjusted gMean ratio (T/R4) and its 2-sided 90% CI. Standard deviation is intra-individual geometric coefficient of variation (%).

Adverse Events

Time Frame	Adverse events (AEs) occurring up to 192 hours after intake of trial drug administration in each treatment period were assigned to treatment.
Adverse Event Reporting Description	The treated set (TS) included all randomized subjects who were documented to have taken at least 1 dose of study drug.
Arm/Group Title	Digoxin (R1)		Furosemide (R2)		Metformin Hydrochloride (R3)		Rosuvastatin (R4)		Test Cocktail (T)
Arm/Group Description	Subjects were administered a single dose of 0.25 milligram (mg) tablet of Digoxin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.		Subjects were administered a single dose of 0.1 milliliter (mL) or 1 mg oral solution of Furosemide orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.		Subjects were administered a single dose of 0.1 mL (10 mg) oral solution of Metformin hydrochloride orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.		Subjects were administered a single dose of 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.		Subjects were administered a single dose of test cocktail (T) comprised of 0.25 mg tablet of Digoxin, 0.1 mL (1 mg) oral solution of Furosemide, 0.1 mL (10 mg) oral solution of Metformin hydrochloride and 10 mg film-coated tablet of Rosuvastatin orally with 320 mL of non-sparkling drinking water after overnight fasting of 10 hours.
All Cause Mortality
	Digoxin (R1)		Furosemide (R2)		Metformin Hydrochloride (R3)		Rosuvastatin (R4)		Test Cocktail (T)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Digoxin (R1)		Furosemide (R2)		Metformin Hydrochloride (R3)		Rosuvastatin (R4)		Test Cocktail (T)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/28 (3.6%)		0/30 (0%)		0/29 (0%)		0/29 (0%)		0/28 (0%)
Injury, poisoning and procedural complications
Exposure to toxic agent	1/28 (3.6%)		0/30 (0%)		0/29 (0%)		0/29 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Digoxin (R1)		Furosemide (R2)		Metformin Hydrochloride (R3)		Rosuvastatin (R4)		Test Cocktail (T)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/30 (0%)		1/29 (3.4%)		1/29 (3.4%)		3/28 (10.7%)
Nervous system disorders
Headache	0/28 (0%)		0/30 (0%)		1/29 (3.4%)		1/29 (3.4%)		3/28 (10.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.