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

Healthy Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03307252
• Other study ID #: 0352-2100
• Secondary ID: 2017-001549-29
• Status: Completed
• Phase: Phase 1
• Start date: October 25, 2017
• Est. completion date: May 2, 2018

Study information

• Verified date: October 2023
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: May 2, 2018
• Est. primary completion date: May 2, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Digoxin
Tablet
• Furosemide
Oral solution
• Metformin
Oral solution
• Rosuvastatin
Film-coated tablet
• Verapamil
Film-coated tablet
• Rifampin
Film-coated tablet
• Cimetidine
Tablet
• Probenecid
Tablet

Locations

Country	Name	City	State
Germany	CTC North GmbH & Co. KG, Hamburg	Hamburg

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Verapamil + R1 (T1) vs. R1)	AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. Geometric mean (gMean) presented here is an adjusted gMean and standard error (SE) presented is a geometric SE (gSE).	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.
Primary	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Rifampin + R1 (T2) vs. R1)	AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Primary	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Cimetidine + R1 (T3) vs. R1)	AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Primary	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) (Probenecid + R1 (T4) vs. R1)	AUC0-tz, area under the concentration-time curve of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) in plasma over the time interval from 0 to the last quantifiable data point is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Primary	Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T1 vs. R1)	Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Primary	Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T2 vs. R1)	Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Primary	Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T3 vs. R1)	Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Primary	Maximum Measured Concentration of the Analytes: Digoxin, Furosemide, Metformin, and Rosuvastatin (Cmax) (T4 vs. R1)	Cmax, maximum measured concentration of the analytes: digoxin, furosemide, metformin, and rosuvastatin (at cocktail doses) is presented. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Secondary	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-8) (T1 vs. R1)	AUC0-8, 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. AUC0-8 not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Secondary	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-8) (T2 vs. R1)	AUC0-8, 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. AUC0-8 not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Secondary	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-8) (T3 vs. R1)	AUC0-8, 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. AUC0-8 not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.
Secondary	Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-8) (T4 vs. R1)	AUC0-8, 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. AUC0-8 not displayed for Digoxin analyte as precision was considered non-sufficient. gMean presented here is an adjusted gMean and SE presented is a gSE.	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.

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