Drug-drug Interaction Between Digoxin, Furosemide, Metformin, and Rosuvastatin

Study Overview
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Brief Summary
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To investigate the mutual interaction potential of digoxin, furosemide, metformin, and rosuvastatin when given alone or together as a cocktail, and to investigate the effect of high doses of metformin or furosemide on pharmacokinetics of the other cocktail compounds

Official Title
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Relative Bioavailability of a Single Oral Dose of Digoxin, Furosemide, Metformin, and Rosuvastatin Given Alone and All Together as a Cocktail, and Investigation of the Effect of Increased Doses of Metformin or Furosemide on Relative Bioavailability of the Other Cocktail Compounds in Healthy Male Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Digoxin
* Drug: Rosuvastatin
* Drug: Digoxin, Furosemide, Metformin hydrochloride, Rosuvastatin
* Drug: Digoxin, Furosemide, Metformin hydrochloride, Rosuvastatin
* Drug: Metformin hydrochloride
* Drug: Digoxin, Furosemide, Metformin hydrochloride, Rosuvastatin
* Drug: Furosemide


Participation Criteria
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Eligibility Criteria
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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, Pulse Rate), 12-lead Electrocardiogram, and clinical laboratory tests Age of 18 to 50 years (incl.) Body Mass Index 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, Pulse Rate, or Electrocardiogram) 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 Surgery of the gastrointestinal tract that could interfere with kinetics 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A (Reference 1) Digoxin<br>1 tablet as single dose, fasted | Drug: Digoxin<br>* single dose, fasted<br>|
| Experimental: B (Reference 2) Furosemide<br>oral solution, as single dose, fasted | Drug: Furosemide<br>* single dose, fasted<br>|
| Experimental: C (Reference 3) Metformin hydrochloride<br>1 film-coated tablet as single dose, fasted | Drug: Metformin hydrochloride<br>* single dose, fasted<br>|
| Experimental: D (Reference 4) Rosuvastatin<br>1 film-coated tablet as single dose, fasted | Drug: Rosuvastatin<br>* single dose, fasted<br>|
| Experimental: E (Test) 1<br>Digoxin (1 tablet), Furosemide (0.5 mL oral solution), Metformin hydrochloride (1 film-coated tablet), Rosuvastatin (1 film-coated tablet), fasted | Drug: Digoxin, Furosemide, Metformin hydrochloride, Rosuvastatin<br>* fasted<br>|
| Experimental: F (Test 2)<br>Digoxin (1 tablet), Furosemide (0.5 mL oral solution), Metformin hydrochloride (2 film-coated tablets), Rosuvastatin (1 film-coated tablet), fasted | Drug: Digoxin, Furosemide, Metformin hydrochloride, Rosuvastatin<br>* fasted<br>|
| Experimental: G (Test 3)<br>Digoxin (1 tablet), Furosemide (2.0 mL oral solution), Metformin hydrochloride (1 film-coated tablet), Rosuvastatin (1 film-coated tablet), fasted | Drug: Digoxin, Furosemide, Metformin hydrochloride, Rosuvastatin<br>* fasted<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Digoxin, Metformin, Rosuvastatin: AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) |  | up to 96 hours | 
| Furosemide: AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) |  | up to 36 hours | 
| Furosemide: Cmax (maximum measured concentration of the analyte in plasma) |  | up to 36 hours | 
| Digoxin, Metformin, Rosuvastatin: Cmax (maximum measured concentration of the analyte in plasma) |  | up to 96 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Furosemide: AUC0-inf (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |  | up to 36 hours | 
| Digoxin, Metformin, Rosuvastatin: AUC0-inf (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |  | up to 96 hours |