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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01111331
First received: April 26, 2010
Last updated: June 25, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Healthy
Drug: BI 10773 25 mg
Drug: Warfarin 25 mg
Drug: Warfarin
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Empagliflozin: Area Under the Curve for the Dosing Interval at Steady State (AUCτ,ss) [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Empagliflozin: Maximum Measured Concentration at Steady State(Cmax,ss) [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Warfarin R-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time of dosing extrapolated to infinity.

  • Warfarin R-enantiomers: Maximum Measured Concentration (Cmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Maximum measured concentration of the analyte in plasma.

  • Warfarin S-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time of dosing extrapolated to infinity.

  • Warfarin S-enantiomers: Maximum Measured Concentration (Cmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Maximum measured concentration of the analyte in plasma


Secondary Outcome Measures:
  • Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N) [ Time Frame: 24 hours after dose 4 or 6 respectively (day 5 and day 7) ] [ Designated as safety issue: No ]
    Plasma concentration of empagliflozin (empa) measured 24 hours after administration of the fourth dose (Cpre,5) and after the sixth dose (Cpre,7).

  • Empagliflozin: Terminal Rate Constant at Steady State (λz,ss) [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Empagliflozin: Terminal Half-life at Steady State (t1/2,ss) [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Empagliflozin: Time to Maximum Plasma Concentration at Steady State (Tmax,ss) [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Empagliflozin: Mean Residence Time at Steady State After Oral Administration (MRTpo,ss) [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Empagliflozin: Apparent Clearance at Steady State (CL/F,ss) [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Empagliflozin: Apparent Volume of Distribution Following Extravascular Administration (Vz/F,ss) [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Warfarin R-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time of dosing to time of last measurable data point.

  • Warfarin R-enantiomers: Time to Maximum Plasma Concentration (Tmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Time from dosing until maximum plasma concentration is reached

  • Warfarin R-enantiomers: Terminal Rate Constant (λz) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Terminal rate constant in plasma

  • Warfarin R-enantiomers: Terminal Half-life (t1/2) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Terminal half-life of the analyte in plasma

  • Warfarin R-enantiomers: Mean Residence Time After Oral Administration (MRTpo) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Mean residence time of the analyte in the body after oral administration

  • Warfarin R-enantiomers: Apparent Clearance After Extravascular Administration (CL/F) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Apparent clearance in plasma after extravascular administration

  • Warfarin R-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Apparent volume of distribution during the terminal phase λz following extravascular administration

  • Warfarin S-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from time of dosing to time of last measurable data point.

  • Warfarin S-enantiomers: Time to Maximum Plasma Concentration (Tmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Time from dosing until maximum plasma concentration is reached

  • Warfarin S-enantiomers: Terminal Rate Constant (λz) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Terminal rate constant in plasma

  • Warfarin S-enantiomers: Terminal Half-life (t1/2) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Terminal half-life of the analyte in plasma

  • Warfarin S-enantiomers: Mean Residence Time After Oral Administration (MRTpo) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Mean residence time of the analyte in the body after oral administration

  • Warfarin S-enantiomers: Apparent Clearance After Extravascular Administration (CL/F) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Apparent clearance in plasma after extravascular administration

  • Warfarin S-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Apparent volume of distribution during the terminal phase λz following extravascular administration

  • Warfarin: Peak International Normalised Ratio (INRmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Peak international normalised ratio for warfarin, measured as the maximum INR over time.

  • Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point (INR AUEC0-tz) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Warfarin: Peak International Normalised Ratio Adjusted to Baseline (INRmax,Base) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Peak international normalised ratio for warfarin adjusted for baseline value (before any trial drug administration) of peak international normalised ratio

  • Warfarin: Peak Prothrombin Time (PTmax) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Peak prothrombin time

  • Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (INR AUEC0-tz,Base) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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

  • Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point (PT AUEC0-tz) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Area under the PT-time curve from time of dosing to time of last measurable data point

  • Warfarin: Peak Prothrombin Time Adjusted to Baseline (PTmax,Base) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Peak prothrombin time adjusted for baseline value (before any trial drug administration) of peak prothrombin

  • Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (PT AUEC0-tz,Base) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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

  • Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by Investigator [ Time Frame: Drug administration until beginning of next sequence/end of trial, 35 days ] [ Designated as safety issue: No ]
    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.


Enrollment: 18
Study Start Date: May 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 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: 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

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria:

Healthy male subjects

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01111331

Locations
Germany
1245.18.1 Boehringer Ingelheim Investigational Site
Biberach, Germany
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01111331     History of Changes
Other Study ID Numbers: 1245.18, 2009-018088-29
Study First Received: April 26, 2010
Results First Received: May 16, 2014
Last Updated: June 25, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Warfarin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014