Transporter Cocktail Mutual Interaction

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

Official Title
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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)

Conditions
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Healthy

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


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 (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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: R1 (Reference 1) Digoxin<br>1 tablet (0.25 mg) digoxin as single dose | Drug: Digoxin<br>* single dose<br>|
| Experimental: R2 Furosemide<br>0.1 mL (1 mg) furosemide oral solution as single dose | Drug: Furosemide<br>* single dose<br>|
| Experimental: R3 Metformin hydrochloride<br>0.1 mL (10 mg) metformin oral solution as single dose | Drug: Metformin<br>* single dose<br>|
| Experimental: R4 Rosuvastatin<br>1 tablet (10 mg) rosuvastatin as single dose | Drug: Rosuvastatin<br>* single dose<br>|
| Experimental: T (Test)<br>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<br>* 0.25 mg digoxin as single dose (all 4 drugs given together as a cocktail at the same time point)<br>Drug: Furosemide<br>* 1 mg furosemide as single dose (all 4 drugs given together as a cocktail at the same time point)<br>Drug: Metformin hydrochloride<br>* 10 mg metformin hydrochloride as single dose (all 4 drugs given together as a cocktail at the same time point)<br>Drug: Rosuvastatin<br>* 10 mg rosuvastatin as single dose (all 4 drugs given together as a cocktail at the same time point)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve of Digoxin From 0 to Last Quantifiable Data Point (AUC 0-tz) | 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. | 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 | 
| Maximum Concentration of Digoxin (Cmax) | This outcome measure presents the maximum measured concentration of digoxin in plasma (Cmax). Standard error presented is actually geometric standard error. | 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 Curve of Furosemide From 0 to Last Quantifiable Data Point (AUC 0-tz) | 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. | 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 | 
| Maximum Concentration of Furosemide (Cmax) | This outcome measure presents the maximum measured concentration of furosemide in plasma (Cmax). Standard error presented is actually geometric standard error. | 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 Curve of Metformin From 0 to Last Quantifiable Data Point (AUC 0-tz) | 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. | 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 | 
| Maximum Concentration of Metformin (Cmax) | This outcome measure presents the maximum measured concentration of metformin in plasma (Cmax). Standard error presented is actually geometric standard error. | 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 Curve of Rosuvastatin From 0 to Last Quantifiable Data Point (AUC 0-tz) | 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. | 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 | 
| Maximum Concentration of Rosuvastatin (Cmax) | This outcome measure presents the maximum measured concentration of rosuvastatin in plasma (Cmax). Standard error presented is actually geometric standard error. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve of Digoxin From 0 Extrapolated to Infinity (AUC 0-∞) | 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. | 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 Curve of Furosemide From 0 Extrapolated to Infinity (AUC 0-∞) | 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. | 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 Curve of Metformin From 0 Extrapolated to Infinity (AUC 0-∞) | 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. | 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 Curve of Rosuvastatin From 0 Extrapolated to Infinity (AUC 0-∞) | 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. | 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 |