Healthy
Conditions
Brief summary
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.
Interventions
DRUGBI 10773 25 mg
25 mg BI 10773 qd for 5 days
DRUGWarfarin 25 mg
25 mg Warfarin single dose
DRUGWarfarin
25 mg warfarin single dose with and without 50 mg BI 10773
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy male subjects
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Empagliflozin: Area Under the Curve for the Dosing Interval at Steady State (AUCτ,ss) | 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. | 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) | 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. | 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-∞) | 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 | Area under the plasma concentration-time curve from time of dosing extrapolated to infinity. |
| Warfarin R-enantiomers: Maximum Measured Concentration (Cmax) | 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 | Maximum measured concentration of the analyte in plasma. |
| Warfarin S-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞) | 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 | Area under the plasma concentration-time curve from time of dosing extrapolated to infinity. |
| Warfarin S-enantiomers: Maximum Measured Concentration (Cmax) | 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 | Maximum measured concentration of the analyte in plasma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Warfarin R-enantiomers: Terminal Rate Constant (λz) | 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 | Terminal rate constant in plasma |
| Empagliflozin: Apparent Volume of Distribution Following Extravascular Administration (Vz/F,ss) | 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 | 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) | 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 | 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) | 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 | Time from dosing until maximum plasma concentration is reached |
| Warfarin R-enantiomers: Terminal Half-life (t1/2) | 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 | Terminal half-life of the analyte in plasma |
| Warfarin R-enantiomers: Mean Residence Time After Oral Administration (MRTpo) | 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 | Mean residence time of the analyte in the body after oral administration |
| Warfarin R-enantiomers: Apparent Clearance After Extravascular Administration (CL/F) | 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 | Apparent clearance in plasma after extravascular administration |
| Warfarin R-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F) | 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 | 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) | 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 | 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) | 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 | Time from dosing until maximum plasma concentration is reached |
| Warfarin S-enantiomers: Terminal Rate Constant (λz) | 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 | Terminal rate constant in plasma |
| Warfarin S-enantiomers: Terminal Half-life (t1/2) | 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 | Terminal half-life of the analyte in plasma |
| Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N) | 24 hours after dose 4 or 6 respectively (day 5 and day 7) | Plasma concentration of empagliflozin (empa) measured 24 hours after administration of the fourth dose (Cpre,5) and after the sixth dose (Cpre,7). |
| Warfarin S-enantiomers: Apparent Clearance After Extravascular Administration (CL/F) | 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 | Apparent clearance in plasma after extravascular administration |
| Warfarin S-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F) | 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 | Apparent volume of distribution during the terminal phase λz following extravascular administration |
| Warfarin: Peak International Normalised Ratio (INRmax) | 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 | 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) | 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 | 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) | 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 | 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) | 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 | Peak prothrombin time |
| Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (INR AUEC0-tz,Base) | 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 | 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) | 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 | 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) | 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 | 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) | 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 | 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 | Drug administration until beginning of next sequence/end of trial, 35 days | 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. |
| Warfarin S-enantiomers: Mean Residence Time After Oral Administration (MRTpo) | 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 | Mean residence time of the analyte in the body after oral administration |
| Empagliflozin: Terminal Rate Constant at Steady State (λz,ss) | 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. | 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) | 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. | 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) | 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 | 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) | 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. | 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) | 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. | 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. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Study Overall Total number of patients randomised and treated in the study. This was a randomised, cross-over, open-label trial consisting of three treatments. 18 patients were randomised to one of two possible treatment sequences. The three treatments were
* Empagliflozin (empa) 25mg given once daily, consisting of a single tablet, on Days 1 to 5
* Empagliflozin (empa) 25mg was given once daily on Days 1 to 7 and warfarin 25mg, consisting of 5 tablets of 5mg, was given as a single dose on Day 1
* Warfarin 25mg was given as a single dose, consisting of 5 individual tablets, on Day 1 | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Study Overall |
|---|---|
| Age, Continuous | 34.8 years STANDARD_DEVIATION 7 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 18 | 5 / 18 | 2 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
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.
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Empagliflozin: Area Under the Curve for the Dosing Interval at Steady State (AUCτ,ss) | 4580.38 nmol*h/L | Geometric Coefficient of Variation 7 |
| Empa Plus Warfarin | Empagliflozin: Area Under the Curve for the Dosing Interval at Steady State (AUCτ,ss) | 4621.37 nmol*h/L | Geometric Coefficient of Variation 7 |
Comparison: Ratio calculated as empa plus warfarin divided by empa90% CI: [96.86, 105.1]ANOVA
Primary
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.
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Empagliflozin: Maximum Measured Concentration at Steady State(Cmax,ss) | 759.96 nmol/L | Geometric Coefficient of Variation 19.9 |
| Empa Plus Warfarin | Empagliflozin: Maximum Measured Concentration at Steady State(Cmax,ss) | 764.82 nmol/L | Geometric Coefficient of Variation 19.9 |
Comparison: Ratio calculated as empa plus warfarin divided by empap-value: 0.002190% CI: [89.79, 112.8]ANOVA
Primary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin R-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞) | 63585.71 ng*h/mL | Geometric Coefficient of Variation 5.7 |
| Empa Plus Warfarin | Warfarin R-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞) | 62626.35 ng*h/mL | Geometric Coefficient of Variation 5.7 |
Comparison: Ratio calculated as empa plus warfarin divided by warfarin90% CI: [95.29, 101.8]ANOVA
Primary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin R-enantiomers: Maximum Measured Concentration (Cmax) | 1404.07 ng/mL | Geometric Coefficient of Variation 12.4 |
| Empa Plus Warfarin | Warfarin R-enantiomers: Maximum Measured Concentration (Cmax) | 1374.40 ng/mL | Geometric Coefficient of Variation 12.4 |
Comparison: Ratio calculated as empa plus warfarin divided by warfarinp-value: 0.000190% CI: [91.12, 105.15]ANOVA
Primary
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.
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin S-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞) | 37493.28 ng*h/mL | Geometric Coefficient of Variation 4.5 |
| Empa Plus Warfarin | Warfarin S-enantiomers: Area Under the Curve 0 to Infinity (AUC0-∞) | 35949.84 ng*h/mL | Geometric Coefficient of Variation 4.5 |
Comparison: Ratio calculated as empa plus warfarin divided by warfarin90% CI: [93.4, 98.43]ANOVA
Primary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin S-enantiomers: Maximum Measured Concentration (Cmax) | 1441.66 ng/mL | Geometric Coefficient of Variation 12.7 |
| Empa Plus Warfarin | Warfarin S-enantiomers: Maximum Measured Concentration (Cmax) | 1425.56 ng/mL | Geometric Coefficient of Variation 12.7 |
Comparison: Ratio calculated as empa plus warfarin divided by warfarinp-value: 0.000190% CI: [91.84, 106.47]ANOVA
Secondary
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
Population: Treated set (TS) included all subjects who had taken at least one dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Empa | Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by Investigator | 0 participants |
| Empa Plus Warfarin | Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by Investigator | 0 participants |
| Empa Plus Warfarin | Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Assessment of Tolerability by Investigator | 0 participants |
Secondary
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.
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Empagliflozin: Apparent Clearance at Steady State (CL/F,ss) | 187 mL/min | Geometric Coefficient of Variation 14.8 |
| Empa Plus Warfarin | Empagliflozin: Apparent Clearance at Steady State (CL/F,ss) | 183 mL/min | Geometric Coefficient of Variation 16.9 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Empagliflozin: Apparent Volume of Distribution Following Extravascular Administration (Vz/F,ss) | 108 L | Geometric Coefficient of Variation 8.63 |
| Empa Plus Warfarin | Empagliflozin: Apparent Volume of Distribution Following Extravascular Administration (Vz/F,ss) | 112 L | Geometric Coefficient of Variation 12.7 |
Secondary
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.
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Empagliflozin: Mean Residence Time at Steady State After Oral Administration (MRTpo,ss) | 8.64 h | Geometric Coefficient of Variation 12.6 |
| Empa Plus Warfarin | Empagliflozin: Mean Residence Time at Steady State After Oral Administration (MRTpo,ss) | 9.08 h | Geometric Coefficient of Variation 17.5 |
Secondary
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)
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa | Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N) | Cpre,5 | 40.8 nmol/L | Geometric Coefficient of Variation 33.4 |
| Empa | Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N) | Cpre,7 | NA nmol/L | — |
| Empa Plus Warfarin | Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N) | Cpre,5 | NA nmol/L | — |
| Empa Plus Warfarin | Empagliflozin: Plasma Concentration 24 Hours After Administration of Dose (C24,N) | Cpre,7 | 41.6 nmol/L | Geometric Coefficient of Variation 36.7 |
Secondary
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.
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Empagliflozin: Terminal Half-life at Steady State (t1/2,ss) | 6.67 h | Geometric Coefficient of Variation 10.6 |
| Empa Plus Warfarin | Empagliflozin: Terminal Half-life at Steady State (t1/2,ss) | 7.07 h | Geometric Coefficient of Variation 11.7 |
Secondary
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.
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Empagliflozin: Terminal Rate Constant at Steady State (λz,ss) | 0.10 1/h | Geometric Coefficient of Variation 10.6 |
| Empa Plus Warfarin | Empagliflozin: Terminal Rate Constant at Steady State (λz,ss) | 0.10 1/h | Geometric Coefficient of Variation 11.7 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Empa | Empagliflozin: Time to Maximum Plasma Concentration at Steady State (Tmax,ss) | 1.50 h | Full Range 35 |
| Empa Plus Warfarin | Empagliflozin: Time to Maximum Plasma Concentration at Steady State (Tmax,ss) | 1.00 h | Full Range 55.5 |
Secondary
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
Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (INR AUEC0-tz,Base) | 32.42 ratio*h | — |
| Empa Plus Warfarin | Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (INR AUEC0-tz,Base) | 36.30 ratio*h | 95% Confidence Interval 55.85 |
Comparison: Difference calculated as empa plus warfarin minus warfarin95% CI: [0.64, 1.95]ANOVA
Secondary
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
Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point (INR AUEC0-tz) | 202.54 ratio*h | — |
| Empa Plus Warfarin | Warfarin: Area Under the INR-time Curve From 0 to Last Measurable Data Point (INR AUEC0-tz) | 178.08 ratio*h | 95% Confidence Interval 10.75 |
Comparison: Difference calculated as empa plus warfarin minus warfarin95% CI: [0.79, 0.98]ANOVA
Secondary
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
Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (PT AUEC0-tz,Base) | 419.24 s*hr | — |
| Empa Plus Warfarin | Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point Adjusted to Baseline (PT AUEC0-tz,Base) | 354.97 s*hr | 95% Confidence Interval 54.49 |
Comparison: Difference calculated as empa plus warfarin minus warfarin95% CI: [0.47, 1.51]ANOVA
Secondary
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
Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point (PT AUEC0-tz) | 2508.34 s*hr | — |
| Empa Plus Warfarin | Warfarin: Area Under the PT-time Curve From 0 to Last Measurable Data Point (PT AUEC0-tz) | 2281.54 s*hr | 95% Confidence Interval 7.61 |
Comparison: Difference calculated as empa plus warfarin minus warfarin95% CI: [0.84, 0.98]ANOVA
Secondary
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
Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin: Peak International Normalised Ratio Adjusted to Baseline (INRmax,Base) | 0.69 Ratio | — |
| Empa Plus Warfarin | Warfarin: Peak International Normalised Ratio Adjusted to Baseline (INRmax,Base) | 0.69 Ratio | 95% Confidence Interval 46.12 |
Comparison: Difference calculated as empa plus warfarin minus warfarin95% CI: [0.67, 1.48]ANOVA
Secondary
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
Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin: Peak International Normalised Ratio (INRmax) | 1.76 Ratio | — |
| Empa Plus Warfarin | Warfarin: Peak International Normalised Ratio (INRmax) | 1.53 Ratio | 95% Confidence Interval 23.68 |
Comparison: Difference calculated as empa plus warfarin minus warfarin95% CI: [0.73, 1.04]ANOVA
Secondary
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
Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin: Peak Prothrombin Time Adjusted to Baseline (PTmax,Base) | 6.69 s | — |
| Empa Plus Warfarin | Warfarin: Peak Prothrombin Time Adjusted to Baseline (PTmax,Base) | 6.51 s | 95% Confidence Interval 41.5 |
Comparison: Difference calculated as empa plus warfarin minus warfarin95% CI: [0.68, 1.4]ANOVA
Secondary
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
Population: Pharmacodynamic (PD) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one PD endpoint without an important protocol violation with respect to the PD evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin: Peak Prothrombin Time (PTmax) | 20.17 s | — |
| Empa Plus Warfarin | Warfarin: Peak Prothrombin Time (PTmax) | 18.07 s | 95% Confidence Interval 17.34 |
Comparison: Difference calculated as empa plus warfarin minus warfarin95% CI: [0.79, 1.02]ANOVA
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin R-enantiomers: Apparent Clearance After Extravascular Administration (CL/F) | 6.55 mL/min | Geometric Coefficient of Variation 20.8 |
| Empa Plus Warfarin | Warfarin R-enantiomers: Apparent Clearance After Extravascular Administration (CL/F) | 6.65 mL/min | Geometric Coefficient of Variation 24.2 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin R-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F) | 26.7 L | Geometric Coefficient of Variation 15.5 |
| Empa Plus Warfarin | Warfarin R-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F) | 26.4 L | Geometric Coefficient of Variation 13.6 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin R-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz) | 58556.93 ng*h/mL | Geometric Coefficient of Variation 5.3 |
| Empa Plus Warfarin | Warfarin R-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz) | 57911.05 ng*h/mL | Geometric Coefficient of Variation 5.3 |
Comparison: Ratio calculated as empa plus warfarin divided by warfarin90% CI: [95.89, 102]ANOVA
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin R-enantiomers: Mean Residence Time After Oral Administration (MRTpo) | 62.9 h | Geometric Coefficient of Variation 16 |
| Empa Plus Warfarin | Warfarin R-enantiomers: Mean Residence Time After Oral Administration (MRTpo) | 61.2 h | Geometric Coefficient of Variation 19.1 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin R-enantiomers: Terminal Half-life (t1/2) | 47.1 h | Geometric Coefficient of Variation 12.1 |
| Empa Plus Warfarin | Warfarin R-enantiomers: Terminal Half-life (t1/2) | 45.8 h | Geometric Coefficient of Variation 15.4 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin R-enantiomers: Terminal Rate Constant (λz) | 0.0147 1/h | Geometric Coefficient of Variation 12.1 |
| Empa Plus Warfarin | Warfarin R-enantiomers: Terminal Rate Constant (λz) | 0.0151 1/h | Geometric Coefficient of Variation 15.4 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin R-enantiomers: Time to Maximum Plasma Concentration (Tmax) | 0.84 h | Full Range 79.5 |
| Empa Plus Warfarin | Warfarin R-enantiomers: Time to Maximum Plasma Concentration (Tmax) | 1.00 h | Full Range 98.7 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin S-enantiomers: Apparent Clearance After Extravascular Administration (CL/F) | 11.1 mL/min | Geometric Coefficient of Variation 17.8 |
| Empa Plus Warfarin | Warfarin S-enantiomers: Apparent Clearance After Extravascular Administration (CL/F) | 11.6 mL/min | Geometric Coefficient of Variation 16.1 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin S-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F) | 35.6 L | Geometric Coefficient of Variation 21.1 |
| Empa Plus Warfarin | Warfarin S-enantiomers: Apparent Volume of Distribution Following Extravascular Administration (Vz/F) | 36.8 L | Geometric Coefficient of Variation 12.7 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin S-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz) | 36386.49 ng*h/mL | Geometric Coefficient of Variation 4.4 |
| Empa Plus Warfarin | Warfarin S-enantiomers: Area Under the Curve 0 to Last Measurable Data Point (AUC0-tz) | 34962.95 ng*h/mL | Geometric Coefficient of Variation 4.4 |
Comparison: Ratio calculated as empa plus warfarin divided by warfarin90% CI: [93.64, 98.6]ANOVA
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin S-enantiomers: Mean Residence Time After Oral Administration (MRTpo) | 40.8 h | Geometric Coefficient of Variation 13.8 |
| Empa Plus Warfarin | Warfarin S-enantiomers: Mean Residence Time After Oral Administration (MRTpo) | 38.9 h | Geometric Coefficient of Variation 15 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin S-enantiomers: Terminal Half-life (t1/2) | 37.0 h | Geometric Coefficient of Variation 13.7 |
| Empa Plus Warfarin | Warfarin S-enantiomers: Terminal Half-life (t1/2) | 36.7 h | Geometric Coefficient of Variation 12.4 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin S-enantiomers: Terminal Rate Constant (λz) | 0.0187 1/h | Geometric Coefficient of Variation 13.7 |
| Empa Plus Warfarin | Warfarin S-enantiomers: Terminal Rate Constant (λz) | 0.0189 1/h | Geometric Coefficient of Variation 12.4 |
Secondary
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
Population: Pharmacokinetic (PK) set included all subjects who had taken at least one dose of trial medication, provided at least one observation for at least one primary PK endpoint without an important protocol violation with respect to the PK evaluation.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Empa | Warfarin S-enantiomers: Time to Maximum Plasma Concentration (Tmax) | 0.68 h | Full Range 74.6 |
| Empa Plus Warfarin | Warfarin S-enantiomers: Time to Maximum Plasma Concentration (Tmax) | 0.84 h | Full Range 85.6 |