Healthy
Conditions
Brief summary
Relative bioavailability of BI 10773 given alone and together with verapamil
Interventions
DRUGVerapamil
single dose verapamil
DRUGBI 10773
single dose BI 10773
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
healthy male and female subjects
Exclusion criteria
Any relevant deviation from healthy conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration (Cmax) | 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration | Maximum measured concentration of empagliflozin (empa) in plasma. |
| 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, 10h, 12h, 24h, 36h, 48h and 72h after drug administration | Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From 0 to Maximum Plasma Concentration (Tmax) | 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration | Time from last dosing to the maximum plasma concentration |
| Terminal Elimination Rate Constant (λz) | 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration | Terminal elimination rate constant in plasma. Note: The numbers provide below for standard deviation are of Coefficient of Variation. |
| Terminal Half-life in Plasma (t1/2) | 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration | Terminal half-life of empagliflozin in plasma. Note: The numbers provide below for standard deviation are of Coefficient of Variation. |
| Mean Residence Time in the Body After Administration (MRTpo) | 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration | Mean residence time of empagliflozin (empa) in the body after oral administration. Note: The numbers provide below for standard deviation are of Coefficient of Variation. |
| Apparent Volume of Distribution Following an Extravascular Dose (Vz/F) | 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration | Apparent volume of distribution during the terminal phase following an extravascular dose. Note: The numbers provide below for standard deviation are of Coefficient of Variation. |
| Clinically Relevant Abnormalities for Physical Examination, Vital Signs, Blood Chemistry and Electrocardiogram (ECG). | Day1 to Day 11 | Clinically relevant abnormalities for physical examination, vital signs , blood chemistry and Electrocardiogram (ECG). New or abnormal findings were reported as adverse events. |
| Assessment of Tolerability by Investigator | Within Day 15 to Day 25 | Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory , bad and not assessable. |
| Apparent Clearance in Plasma After Extravascular Administration (CL/F) | 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration | Apparent clearance of empagliflozin (empa) in plasma after extravascular administration. Note: The numbers provide below for standard deviation are of Coefficient of Variation. |
| Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz) | 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration | Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to time of last quantifiable data point. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Verapamil Plasma Concentration | Predose and 1 hour (h), 25h, 49h and 73h after verapamil administration | Verapamil plasma concentration were measured in order to confirm exposure. Note: No descriptive statistics was calculated for predose, 49.0 (h) and 73.0 (h), as most of the values were below the limit of quantification (BLQ). |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population An open label, randomised, two-period crossover trial. The two treatments administered were
* A single dose of empagliflozin (empa) 25 mg
* A single dose of empagliflozin (empa) 25 mg one hour after administration of a single dose of 120mg verapamil
The two treatment periods were separated by a washout period of at least 7 days. | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 34.3 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 16 | 9 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Curve 0 to Infinity (AUC0-∞)
Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity.
Time frame: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had 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 | Area Under the Curve 0 to Infinity (AUC0-∞) | 5190 nmol*h/L | Geometric Coefficient of Variation 25 |
| Empa Plus Verapamil | Area Under the Curve 0 to Infinity (AUC0-∞) | 5340 nmol*h/L | Geometric Coefficient of Variation 25.5 |
Comparison: Ratio calculated as empa plus verapamil divided by empa90% CI: [98.87, 107.02]ANOVA
Primary
Maximum Measured Concentration (Cmax)
Maximum measured concentration of empagliflozin (empa) in plasma.
Time frame: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had 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 | Maximum Measured Concentration (Cmax) | 785 nmol | Geometric Coefficient of Variation 31.5 |
| Empa Plus Verapamil | Maximum Measured Concentration (Cmax) | 725 nmol | Geometric Coefficient of Variation 29.1 |
Comparison: Ratio calculated as empa plus verapamil divided by empa90% CI: [85.38, 99.97]ANOVA
Secondary
Apparent Clearance in Plasma After Extravascular Administration (CL/F)
Apparent clearance of empagliflozin (empa) in plasma after extravascular administration. Note: The numbers provide below for standard deviation are of Coefficient of Variation.
Time frame: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had 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 | Apparent Clearance in Plasma After Extravascular Administration (CL/F) | 178 mL/min | Geometric Coefficient of Variation 25 |
| Empa Plus Verapamil | Apparent Clearance in Plasma After Extravascular Administration (CL/F) | 173 mL/min | Geometric Coefficient of Variation 25.5 |
Secondary
Apparent Volume of Distribution Following an Extravascular Dose (Vz/F)
Apparent volume of distribution during the terminal phase following an extravascular dose. Note: The numbers provide below for standard deviation are of Coefficient of Variation.
Time frame: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had 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 | Apparent Volume of Distribution Following an Extravascular Dose (Vz/F) | 186 L | Geometric Coefficient of Variation 31.8 |
| Empa Plus Verapamil | Apparent Volume of Distribution Following an Extravascular Dose (Vz/F) | 195 L | Geometric Coefficient of Variation 28.8 |
Secondary
Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to time of last quantifiable data point.
Time frame: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had 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 | Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz) | 5140 nmol*h/L | Geometric Coefficient of Variation 25 |
| Empa Plus Verapamil | Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz) | 5280 nmol*h/L | Geometric Coefficient of Variation 25.7 |
Comparison: Ratio calculated as empa plus verapamil divided by empa90% CI: [98.87, 106.83]ANOVA
Secondary
Assessment of Tolerability by Investigator
Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory , bad and not assessable.
Time frame: Within Day 15 to Day 25
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Empa | Assessment of Tolerability by Investigator | Satisfactory | 0.0 percentage of participants |
| Empa | Assessment of Tolerability by Investigator | Bad | 0.0 percentage of participants |
| Empa | Assessment of Tolerability by Investigator | Not Satisfactory | 0.0 percentage of participants |
| Empa | Assessment of Tolerability by Investigator | Not assessable | 0.0 percentage of participants |
| Empa | Assessment of Tolerability by Investigator | Good | 100.0 percentage of participants |
| Empa Plus Verapamil | Assessment of Tolerability by Investigator | Not assessable | 0.0 percentage of participants |
| Empa Plus Verapamil | Assessment of Tolerability by Investigator | Good | 87.5 percentage of participants |
| Empa Plus Verapamil | Assessment of Tolerability by Investigator | Satisfactory | 6.3 percentage of participants |
| Empa Plus Verapamil | Assessment of Tolerability by Investigator | Not Satisfactory | 6.3 percentage of participants |
| Empa Plus Verapamil | Assessment of Tolerability by Investigator | Bad | 0.0 percentage of participants |
Secondary
Clinically Relevant Abnormalities for Physical Examination, Vital Signs, Blood Chemistry and Electrocardiogram (ECG).
Clinically relevant abnormalities for physical examination, vital signs , blood chemistry and Electrocardiogram (ECG). New or abnormal findings were reported as adverse events.
Time frame: Day1 to Day 11
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, Blood Chemistry and Electrocardiogram (ECG). | 0 participants |
| Empa Plus Verapamil | Clinically Relevant Abnormalities for Physical Examination, Vital Signs, Blood Chemistry and Electrocardiogram (ECG). | 0 participants |
Secondary
Mean Residence Time in the Body After Administration (MRTpo)
Mean residence time of empagliflozin (empa) in the body after oral administration. Note: The numbers provide below for standard deviation are of Coefficient of Variation.
Time frame: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had 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 | Mean Residence Time in the Body After Administration (MRTpo) | 9.47 h | Geometric Coefficient of Variation 12 |
| Empa Plus Verapamil | Mean Residence Time in the Body After Administration (MRTpo) | 9.95 h | Geometric Coefficient of Variation 13.8 |
Secondary
Terminal Elimination Rate Constant (λz)
Terminal elimination rate constant in plasma. Note: The numbers provide below for standard deviation are of Coefficient of Variation.
Time frame: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had 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 | Terminal Elimination Rate Constant (λz) | 0.0573 1/h | Geometric Coefficient of Variation 29.2 |
| Empa Plus Verapamil | Terminal Elimination Rate Constant (λz) | 0.0531 1/h | Geometric Coefficient of Variation 30.2 |
Secondary
Terminal Half-life in Plasma (t1/2)
Terminal half-life of empagliflozin in plasma. Note: The numbers provide below for standard deviation are of Coefficient of Variation.
Time frame: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had 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 | Terminal Half-life in Plasma (t1/2) | 12.1 h | Geometric Coefficient of Variation 29.2 |
| Empa Plus Verapamil | Terminal Half-life in Plasma (t1/2) | 13.1 h | Geometric Coefficient of Variation 30.2 |
Secondary
Time From 0 to Maximum Plasma Concentration (Tmax)
Time from last dosing to the maximum plasma concentration
Time frame: 0 hours (h), 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration
Population: Pharmacokinetic (PK) set: All subjects who had taken at least one dose of trial medication, who had 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) |
|---|---|---|
| Empa | Time From 0 to Maximum Plasma Concentration (Tmax) | 1.50 h |
| Empa Plus Verapamil | Time From 0 to Maximum Plasma Concentration (Tmax) | 1.75 h |
Other Pre-specified
Verapamil Plasma Concentration
Verapamil plasma concentration were measured in order to confirm exposure. Note: No descriptive statistics was calculated for predose, 49.0 (h) and 73.0 (h), as most of the values were below the limit of quantification (BLQ).
Time frame: Predose and 1 hour (h), 25h, 49h and 73h after verapamil administration
Population: Treated set (TS) included all subjects who had taken at least one dose of trial medication.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa | Verapamil Plasma Concentration | Planned time: 1.0 (h) | 94.5 ng/mL | Geometric Coefficient of Variation 76.3 |
| Empa | Verapamil Plasma Concentration | Planned time: 25.0(h) (included 11 participants) | 2.69 ng/mL | Geometric Coefficient of Variation 82.2 |