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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 10773 25 mg
* Drug: Warfarin 25 mg
* Drug: BI 10773 25 mg
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy male subjects

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

What is the study measuring?
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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 |