Drug Drug Interaction of Empagliflozin (BI 10773) and Warfarin in Healthy Volunteers

Relative Bioavailability of Both BI 10773 and Warfarin and Pharmacodynamics of Warfarin After Co-administration Compared to Multiple Oral Doses of BI 10773 (25 mg Once Daily) and a Single Oral Dose of Warfarin (25 mg) Alone in Healthy Male Volunteers (an Open-label, Crossover, Clinical Phase I Study)

The objective of the current study is to investigate the bioavailability of BI 10773 and of warfarin after concomitant multiple oral administration of BI 10773 and a single oral dose of warfarin in comparison to BI 10773 and warfarin given alone, and to investigate the pharmacodynamics of a single oral dose of warfarin with and without concomitant multiple oral administration of BI 10773.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: BI 10773 25 mg; Drug: BI 10773 25 mg; Drug: Warfarin 25 mg; Drug: Warfarin

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Biberach, Germany
    • 1245.18.1 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: Male

Description

Inclusion criteria:

Healthy male subjects

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 25 mg; 1 tablet 25 mg BI 10773 qd for 5 days	Drug: BI 10773 25 mg; 25 mg BI 10773 qd for 5 days; Drug: BI 10773 25 mg; 25 mg BI 10773 qd for 12 days
Experimental: BI 10773 25 mg + Warfarin 25 mg; 1 tablet 25 mg BI 10773 qd for 7 days plus 5 tablets 5 mg warfarin single dose	Drug: BI 10773 25 mg; 25 mg BI 10773 qd for 5 days; Drug: BI 10773 25 mg; 25 mg BI 10773 qd for 12 days; Drug: Warfarin 25 mg; 25 mg Warfarin single dose
Active Comparator: Warfarin 25 mg; 5 tablets 5 mg warfarin single dose	Drug: Warfarin; 25 mg warfarin single dose with and without 50 mg BI 10773

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Empagliflozin: Area Under the Curve for the Dosing Interval at Steady State (AUCτ,ss)	Area under the plasma concentration-time curve for the dosing interval τ at steady state In addition to the specified time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.
Empagliflozin: Maximum Measured Concentration at Steady State(Cmax,ss)	Maximum measured plasma concentration of empagliflozin (empa) for the dosing interval τ at steady state. In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.
Warfarin R-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞)	Area under the plasma concentration-time curve from time of dosing extrapolated to infinity.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin R-enantiomers: Maximum Measured Concentration (Cmax)	Maximum measured concentration of the analyte in plasma.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin S-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞)	Area under the plasma concentration-time curve from time of dosing extrapolated to infinity.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin S-enantiomers: Maximum Measured Concentration (Cmax)	Maximum measured concentration of the analyte in plasma	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N)	Plasma concentration of empagliflozin (empa) measured 24 hours after administration of the fourth dose (Cpre,5) and after the sixth dose (Cpre,7).	24 hours after dose 4 or 6 respectively (day 5 and day 7)
Empagliflozin: Terminal Rate Constant at Steady State (λz,ss)	Terminal rate constant of empagliflozin (empa) in plasma at steady state. In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.
Empagliflozin: Terminal Half-life at Steady State (t1/2,ss)	Terminal half-life of empagliflozin (empa) in plasma at steady state. In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.
Empagliflozin: Time to Maximum Plasma Concentration at Steady State (Tmax,ss)	Time from last dosing to maximum plasma concentration at steady state over a uniform dosing interval τ. In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin
Empagliflozin: Mean Residence Time at Steady State After Oral Administration (MRTpo,ss)	Mean residence time of empagliflozin (empa) in the body at steady state after oral administration. In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.
Empagliflozin: Apparent Clearance at Steady State (CL/F,ss)	Apparent clearance in plasma after extravascular administration at steady state. In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin.
Empagliflozin: Apparent Volume of Distribution Following Extravascular Administration (Vz/F,ss)	Apparent volume of distribution during the terminal phase at steady state following extravascular administration. In addition to the below time frame, pre-dose samples were collected on Days 1, 3, and 4 for empa and a post-dose sample on day 1 for empa plus warfarin.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h post-dose on Day 5 for for empa; 0h, 20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h for empa plus warfarin
Warfarin R-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz)	Area under the plasma concentration-time curve from time of dosing to time of last measurable data point.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin R-enantiomers: Time to Maximum Plasma Concentration (Tmax)	Time from dosing until maximum plasma concentration is reached	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin R-enantiomers: Terminal Rate Constant (λz)	Terminal rate constant in plasma	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin R-enantiomers: Terminal Half-life (t1/2)	Terminal half-life of the analyte in plasma	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin R-enantiomers: Mean Residence Time After Oral Administration (MRTpo)	Mean residence time of the analyte in the body after oral administration	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin R-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)	Apparent clearance in plasma after extravascular administration	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin R-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)	Apparent volume of distribution during the terminal phase λz following extravascular administration	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin S-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz)	Area under the plasma concentration-time curve from time of dosing to time of last measurable data point.	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin S-enantiomers: Time to Maximum Plasma Concentration (Tmax)	Time from dosing until maximum plasma concentration is reached	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin S-enantiomers: Terminal Rate Constant (λz)	Terminal rate constant in plasma	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin S-enantiomers: Terminal Half-life (t1/2)	Terminal half-life of the analyte in plasma	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin S-enantiomers: Mean Residence Time After Oral Administration (MRTpo)	Mean residence time of the analyte in the body after oral administration	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin S-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)	Apparent clearance in plasma after extravascular administration	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin S-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)	Apparent volume of distribution during the terminal phase λz following extravascular administration	0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin: Peak International Normalised Ratio (INRmax)	Peak international normalised ratio for warfarin, measured as the maximum INR over time.	0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point (INR AUEC0-tz)	Area under the concentration time curve of the INR measurements over the time interval from 0 to the time of the last quantifiable data point.	0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin: Peak International Normalised Ratio Adjusted to Baseline (INRmax,Base)	Peak international normalised ratio for warfarin adjusted for baseline value (before any trial drug administration) of peak international normalised ratio	0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin: Peak Prothrombin Time (PTmax)	Peak prothrombin time	0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (INR AUEC0-tz,Base)	Area under the INR-time curve from time of dosing to time of last measurable data point adjusted for baseline value (before any trial drug administration) of area under the INR-time curve	0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point (PT AUEC0-tz)	Area under the PT-time curve from time of dosing to time of last measurable data point	0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin: Peak Prothrombin Time Adjusted to Baseline (PTmax,Base)	Peak prothrombin time adjusted for baseline value (before any trial drug administration) of peak prothrombin	0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (PT AUEC0-tz,Base)	Area under the PT-time curve from time of dosing to time of last measurable data point adjusted for baseline value (before any trial drug administration) of area under the PT-time curve	0 hours (h), 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h, 168h after administration of warfarin for both warfarin alone and warfarin plus empagliflozin
Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by Investigator	Clinically relevant abnormalities for physical examination, vital signs, ECG, blood chemistry and assessment of tolerability by investigator. New abnormal findings or worsening of baseline conditions were reported as Adverse Events.	Drug administration until beginning of next sequence/end of trial, 35 days

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

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Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: April 26, 2010
• First Submitted That Met QC Criteria: April 26, 2010
• First Posted (Estimate): April 27, 2010

Study Record Updates

• Last Update Posted (Estimate): July 23, 2014
• Last Update Submitted That Met QC Criteria: June 25, 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; Anticoagulants; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin; Warfarin
• Other Study ID Numbers: 1245.18; 2009-018088-29 (EudraCT Number: EudraCT)