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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
25 mg BI 10773 qd for 5 days
25 mg Warfarin single dose
25 mg BI 10773 qd for 12 days
1245.18.1 Boehringer Ingelheim Investigational Site
Biberach, Germany
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.
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.
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.
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.
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.
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
Warfarin R-enantiomers: Maximum Measured Concentration (Cmax)
Maximum measured concentration of the analyte in plasma.
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
Warfarin S-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞)
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25 mg warfarin single dose with and without 50 mg BI 10773
Area under the plasma concentration-time curve from time of dosing extrapolated to infinity.
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
Warfarin S-enantiomers: Maximum Measured Concentration (Cmax)
Maximum measured concentration of the analyte in plasma
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
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).
Time frame: 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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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
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.
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
Warfarin R-enantiomers: Time to Maximum Plasma Concentration (Tmax)
Time from dosing until maximum plasma concentration is reached
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
Warfarin R-enantiomers: Terminal Rate Constant (λz)
Terminal rate constant in plasma
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
Warfarin R-enantiomers: Terminal Half-life (t1/2)
Terminal half-life of the analyte in plasma
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
Warfarin R-enantiomers: Mean Residence Time After Oral Administration (MRTpo)
Mean residence time of the analyte in the body after oral administration
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
Warfarin R-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)
Apparent clearance in plasma after extravascular administration
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
Warfarin R-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)
Apparent volume of distribution during the terminal phase λz following extravascular administration
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
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.
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
Warfarin S-enantiomers: Time to Maximum Plasma Concentration (Tmax)
Time from dosing until maximum plasma concentration is reached
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
Warfarin S-enantiomers: Terminal Rate Constant (λz)
Terminal rate constant in plasma
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
Warfarin S-enantiomers: Terminal Half-life (t1/2)
Terminal half-life of the analyte in plasma
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
Warfarin S-enantiomers: Mean Residence Time After Oral Administration (MRTpo)
Mean residence time of the analyte in the body after oral administration
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
Warfarin S-enantiomers: Apparent Clearance After Extravascular Administration (CL/F)
Apparent clearance in plasma after extravascular administration
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
Warfarin S-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F)
Apparent volume of distribution during the terminal phase λz following extravascular administration
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
Warfarin: Peak International Normalised Ratio (INRmax)
Peak international normalised ratio for warfarin, measured as the maximum INR over time.
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
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.
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
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
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
Warfarin: Peak Prothrombin Time (PTmax)
Peak prothrombin time
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
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
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
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
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
Warfarin: Peak Prothrombin Time Adjusted to Baseline (PTmax,Base)
Peak prothrombin time adjusted for baseline value (before any trial drug administration) of peak prothrombin
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
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
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
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.
Time frame: Drug administration until beginning of next sequence/end of trial, 35 days