Relative Bioavailability of Empagliflozin (BI 10773) and Ramipril Administered Together Compared to Empagliflozin (BI 10773) and Ramipril Alone in Healthy Volunteers

Relative Bioavailability of Multiple Oral Doses of BI 10773 (25 mg) and Ramipril (5 mg) Administered Together Compared to Multiple Oral Doses of BI 10773 (25 mg) Alone and Ramipril (5 mg) Alone in Healthy Male and Female Volunteers (an Open Label, Randomised, Three Way Crossover, Clinical Phase I Study)

Primary objective:To investigate if BI 10773 affects the pharmacokinetics of ramipril and if ramipril affects the pharmacokinetics of BI 10773.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: BI 10773; Drug: BI 10773; Drug: Ramipril; Drug: Ramipril

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Biberach, Germany
    • 1245.45.1 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. healthy male and female subjects

Exclusion criteria:

1. Any relevant deviation from healthy conditions.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 10773; 1 tablet per days for 5 days, oral administration with 240 mL water for each treatment	Drug: BI 10773; medium dose, oral administration; Drug: BI 10773; medium dose oral administration
Other: Ramipril; 1 tablet on day 1 and 2 tablets per day on day 2-5, oral administration with 240 mL water for each treatment	Drug: Ramipril; Medium dose oral administration on day 2-5; Drug: Ramipril; Low dose oral administration on day 1
Other: BI 10773 + Ramipril; 1 tablet BI 10773 and 1 tablet on day 1 and 2 tablets ramipril per day on day 2-5, oral administration with 240 mL water for each treatment	Drug: BI 10773; medium dose, oral administration; Drug: BI 10773; medium dose oral administration; Drug: Ramipril; Medium dose oral administration on day 2-5; Drug: Ramipril; Low dose oral administration on day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Empa: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss)	Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of empagliflozin (empa).	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Total Empa: Maximum Measured Concentration (Cmax,ss)	Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of empagliflozin (empa).	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Total Ramipril: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss).	Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramipril.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Total Ramipril: Maximum Measured Concentration (Cmax,ss)	Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramipril.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Total Ramiprilat: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss).	Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramiprilat (active metabolite of ramipril).	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Total Ramiprilat: Maximum Measured Concentration (Cmax,ss)	Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramiprilat.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)	Predose concentration of the analyte in plasma prior to administration of the Nth dose, of empagliflozin.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)	Predose concentration of the analyte in plasma prior to administration of the Nth dose, of ramiprilat. Note, predose concentrations for ramipril were all below the limit of quantification (BLQ) and therefore the predose concentration of the analyte in plasma prior to administration of the Nth dose, of ramipril was not analysed.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss)	Time from last dosing to the maximum measured concentration of the analyte in plasma at steady state.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Terminal Rate Constant (λz,ss)	Terminal rate constant in plasma at steady-state	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Terminal Half-life (T 1/2,ss)	Terminal half-life of the analyte in plasma at steady-state.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Mean Residence Time (MRTpo,ss)	Mean residence time of the analyte in the body after oral administration at steady-state.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Apparent Clearance After Extravascular Administration (CL/Fss)	Apparent clearance of the analyte in plasma after extravascular administration at steady-state.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Apparent Volume of Distribution During the Terminal Phase (Vz/Fss)	Apparent volume of distribution at steady-state during the terminal phase λz following an extravascular dose.	0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability	Clinically relevant abnormalities for physical examination, vital signs, ECG, blood chemistry and assessment tolerability by the investigator. New abnormal findings or worsening of baseline conditions were reported as adverse events.	From drug administration until end of washout period (36 days)

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Macha S, Sennewald R, Rose P, Schoene K, Pinnetti S, Woerle HJ, Broedl UC. Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. Clin Ther. 2013 Mar;35(3):226-35. doi: 10.1016/j.clinthera.2013.02.015.

Helpful Links

• Related Info
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Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: January 20, 2011
• First Submitted That Met QC Criteria: January 26, 2011
• First Posted (Estimate): January 27, 2011

Study Record Updates

• Last Update Posted (Estimate): July 22, 2014
• Last Update Submitted That Met QC Criteria: June 23, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Empagliflozin; Ramipril
• Other Study ID Numbers: 1245.45; 2010-022717-25 (EudraCT Number: EudraCT)