Healthy
Conditions
Brief summary
Primary objective:To investigate if BI 10773 affects the pharmacokinetics of ramipril and if ramipril affects the pharmacokinetics of BI 10773.
Interventions
DRUGBI 10773
medium dose, oral administration
DRUGRamipril
Medium dose oral administration on day 2-5
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1\. healthy male and female subjects
Exclusion criteria
1\. Any relevant deviation from healthy conditions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Empa: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of empagliflozin (empa). |
| Total Empa: Maximum Measured Concentration (Cmax,ss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of empagliflozin (empa). |
| Total Ramipril: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramipril. |
| Total Ramipril: Maximum Measured Concentration (Cmax,ss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramipril. |
| Total Ramiprilat: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramiprilat (active metabolite of ramipril). |
| Total Ramiprilat: Maximum Measured Concentration (Cmax,ss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramiprilat. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Clearance After Extravascular Administration (CL/Fss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Apparent clearance of the analyte in plasma after extravascular administration at steady-state. |
| Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Predose concentration of the analyte in plasma prior to administration of the Nth dose, of empagliflozin. |
| Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability | From drug administration until end of washout period (36 days) | Clinically relevant abnormalities for physical examination, vital signs, ECG, blood chemistry and assessment tolerability by the investigator. New abnormal findings or worsening of baseline conditions were reported as adverse events. |
| Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Apparent volume of distribution at steady-state during the terminal phase λz following an extravascular dose. |
| Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Predose concentration of the analyte in plasma prior to administration of the Nth dose, of ramiprilat. Note, predose concentrations for ramipril were all below the limit of quantification (BLQ) and therefore the predose concentration of the analyte in plasma prior to administration of the Nth dose, of ramipril was not analysed. |
| Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Time from last dosing to the maximum measured concentration of the analyte in plasma at steady state. |
| Terminal Rate Constant (λz,ss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Terminal rate constant in plasma at steady-state |
| Terminal Half-life (T 1/2,ss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Terminal half-life of the analyte in plasma at steady-state. |
| Mean Residence Time (MRTpo,ss) | 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4 | Mean residence time of the analyte in the body after oral administration at steady-state. |
Countries
Germany
Participant flow
Pre-assignment details
This was a randomised, open-label, three period, crossover study. Each treatment period was 8 days, with drug administration on days 1 to 5, and they were separated by a washout period of at least 7 days between drug administrations of 2 subsequent treatments.
Participants by arm
| Arm | Count |
|---|---|
| Study Overall A randomised, open-label, three period, crossover study. The three treatments administered were
* Empagliflozin alone
* Ramipril
* Empagliflozin plus Ramipril
Each treatment period was 8 days, with drug administration on days 1 to 5, and they were separated by a washout period of at least 7 days between drug administrations of 2 subsequent treatments. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Washout Period 1 (7 Days) | Required unexpected medical treatment | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Study Overall |
|---|---|
| Age, Continuous | 38.0 years STANDARD_DEVIATION 11.3 |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 8 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 | 1 / 22 | 3 / 22 | 2 / 23 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 23 |
Outcome results
Primary
Total Empa: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss)
Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of empagliflozin (empa).
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa Alone | Total Empa: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss) | 5850 nmol*h/L | Geometric Coefficient of Variation 18.1 |
| Empa + Ramipril | Total Empa: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss) | 5680 nmol*h/L | Geometric Coefficient of Variation 16.3 |
90% CI: [93.05, 100.18]ANOVA
Primary
Total Empa: Maximum Measured Concentration (Cmax,ss)
Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of empagliflozin (empa).
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa Alone | Total Empa: Maximum Measured Concentration (Cmax,ss) | 874 nmol/L | Geometric Coefficient of Variation 25.9 |
| Empa + Ramipril | Total Empa: Maximum Measured Concentration (Cmax,ss) | 911 nmol/L | Geometric Coefficient of Variation 21.1 |
90% CI: [97.65, 111.77]ANOVA
Primary
Total Ramipril: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss).
Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramipril.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa Alone | Total Ramipril: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). | 6.59 ng*h/mL | Geometric Coefficient of Variation 37 |
| Empa + Ramipril | Total Ramipril: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). | 7.27 ng*h/mL | Geometric Coefficient of Variation 37.8 |
90% CI: [100.51, 116.35]ANOVA
Primary
Total Ramiprilat: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss).
Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramiprilat (active metabolite of ramipril).
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa Alone | Total Ramiprilat: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). | 87.2 ng*h/mL | Geometric Coefficient of Variation 15.5 |
| Empa + Ramipril | Total Ramiprilat: Area Under the Curve at Steady-state Over a Uniform Dosing Interval (AUCτ,ss). | 85.1 ng*h/mL | Geometric Coefficient of Variation 20.1 |
90% CI: [96, 101.42]ANOVA
Primary
Total Ramiprilat: Maximum Measured Concentration (Cmax,ss)
Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramiprilat.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa Alone | Total Ramiprilat: Maximum Measured Concentration (Cmax,ss) | 11.2 ng/mL | Geometric Coefficient of Variation 36.8 |
| Empa + Ramipril | Total Ramiprilat: Maximum Measured Concentration (Cmax,ss) | 10.5 ng/mL | Geometric Coefficient of Variation 46.6 |
90% CI: [92.67, 104.25]ANOVA
Primary
Total Ramipril: Maximum Measured Concentration (Cmax,ss)
Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramipril.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa Alone | Total Ramipril: Maximum Measured Concentration (Cmax,ss) | 8.42 ng/mL | Geometric Coefficient of Variation 45.6 |
| Empa + Ramipril | Total Ramipril: Maximum Measured Concentration (Cmax,ss) | 8.97 ng/mL | Geometric Coefficient of Variation 53.6 |
90% CI: [89.73, 119.64]ANOVA
Secondary
Apparent Clearance After Extravascular Administration (CL/Fss)
Apparent clearance of the analyte in plasma after extravascular administration at steady-state.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa Alone | Apparent Clearance After Extravascular Administration (CL/Fss) | Total ramipril | NA mL/min | — |
| Empa Alone | Apparent Clearance After Extravascular Administration (CL/Fss) | Total empa | 158 mL/min | Geometric Coefficient of Variation 18.1 |
| Empa Alone | Apparent Clearance After Extravascular Administration (CL/Fss) | Total ramiprilat | NA mL/min | — |
| Empa + Ramipril | Apparent Clearance After Extravascular Administration (CL/Fss) | Total ramipril | 12600 mL/min | Geometric Coefficient of Variation 37 |
| Empa + Ramipril | Apparent Clearance After Extravascular Administration (CL/Fss) | Total empa | NA mL/min | — |
| Empa + Ramipril | Apparent Clearance After Extravascular Administration (CL/Fss) | Total ramiprilat | 955 mL/min | Geometric Coefficient of Variation 15.5 |
| Empa + Ramipril | Apparent Clearance After Extravascular Administration (CL/Fss) | Total empa | 163 mL/min | Geometric Coefficient of Variation 16.3 |
| Empa + Ramipril | Apparent Clearance After Extravascular Administration (CL/Fss) | Total ramiprilat | 979 mL/min | Geometric Coefficient of Variation 20.1 |
| Empa + Ramipril | Apparent Clearance After Extravascular Administration (CL/Fss) | Total ramipril | 11500 mL/min | Geometric Coefficient of Variation 37.8 |
Secondary
Apparent Volume of Distribution During the Terminal Phase (Vz/Fss)
Apparent volume of distribution at steady-state during the terminal phase λz following an extravascular dose.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa Alone | Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Total ramipril | NA L | — |
| Empa Alone | Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Total empa | 174 L | Geometric Coefficient of Variation 31.8 |
| Empa Alone | Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Total ramiprilat | NA L | — |
| Empa + Ramipril | Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Total ramipril | 2910 L | Geometric Coefficient of Variation 89.1 |
| Empa + Ramipril | Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Total empa | NA L | — |
| Empa + Ramipril | Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Total ramiprilat | 6050 L | Geometric Coefficient of Variation 32 |
| Empa + Ramipril | Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Total empa | 196 L | Geometric Coefficient of Variation 40 |
| Empa + Ramipril | Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Total ramiprilat | 6460 L | Geometric Coefficient of Variation 42.5 |
| Empa + Ramipril | Apparent Volume of Distribution During the Terminal Phase (Vz/Fss) | Total ramipril | 2310 L | Geometric Coefficient of Variation 97.3 |
Secondary
Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability
Clinically relevant abnormalities for physical examination, vital signs, ECG, blood chemistry and assessment tolerability by the investigator. New abnormal findings or worsening of baseline conditions were reported as adverse events.
Time frame: From drug administration until end of washout period (36 days)
Population: Treated set which included all subjects who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Empa Alone | Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability | 0 participants |
| Empa + Ramipril | Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability | 0 participants |
| Empa + Ramipril | Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability | 0 participants |
Secondary
Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Predose concentration of the analyte in plasma prior to administration of the Nth dose, of empagliflozin.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa Alone | Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,2 | 40.3 nmol/L | Geometric Coefficient of Variation 31 |
| Empa Alone | Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,3 | 45.8 nmol/L | Geometric Coefficient of Variation 33.7 |
| Empa Alone | Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,4 | 49.2 nmol/L | Geometric Coefficient of Variation 29.5 |
| Empa Alone | Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,5 | 47.8 nmol/L | Geometric Coefficient of Variation 25.5 |
| Empa + Ramipril | Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,5 | 48.3 nmol/L | Geometric Coefficient of Variation 27.9 |
| Empa + Ramipril | Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,2 | 38.6 nmol/L | Geometric Coefficient of Variation 32.1 |
| Empa + Ramipril | Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,4 | 46.4 nmol/L | Geometric Coefficient of Variation 27.2 |
| Empa + Ramipril | Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,3 | 45.1 nmol/L | Geometric Coefficient of Variation 30.6 |
Secondary
Mean Residence Time (MRTpo,ss)
Mean residence time of the analyte in the body after oral administration at steady-state.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa Alone | Mean Residence Time (MRTpo,ss) | Total ramipril | NA hours | — |
| Empa Alone | Mean Residence Time (MRTpo,ss) | Total empa | 9.95 hours | Geometric Coefficient of Variation 18 |
| Empa Alone | Mean Residence Time (MRTpo,ss) | Total ramiprilat | NA hours | — |
| Empa + Ramipril | Mean Residence Time (MRTpo,ss) | Total ramipril | 1.29 hours | Geometric Coefficient of Variation 54.2 |
| Empa + Ramipril | Mean Residence Time (MRTpo,ss) | Total empa | NA hours | — |
| Empa + Ramipril | Mean Residence Time (MRTpo,ss) | Total ramiprilat | 44.7 hours | Geometric Coefficient of Variation 29.9 |
| Empa + Ramipril | Mean Residence Time (MRTpo,ss) | Total empa | 9.68 hours | Geometric Coefficient of Variation 16.8 |
| Empa + Ramipril | Mean Residence Time (MRTpo,ss) | Total ramiprilat | 47.1 hours | Geometric Coefficient of Variation 38.7 |
| Empa + Ramipril | Mean Residence Time (MRTpo,ss) | Total ramipril | 1.42 hours | Geometric Coefficient of Variation 57.8 |
Secondary
Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Predose concentration of the analyte in plasma prior to administration of the Nth dose, of ramiprilat. Note, predose concentrations for ramipril were all below the limit of quantification (BLQ) and therefore the predose concentration of the analyte in plasma prior to administration of the Nth dose, of ramipril was not analysed.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa Alone | Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,2 | 1.03 ng/mL | Geometric Coefficient of Variation 25.5 |
| Empa Alone | Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,3 | 1.33 ng/mL | Geometric Coefficient of Variation 21.9 |
| Empa Alone | Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,4 | 1.39 ng/mL | Geometric Coefficient of Variation 20.7 |
| Empa Alone | Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,5 | 1.45 ng/mL | Geometric Coefficient of Variation 23.4 |
| Empa + Ramipril | Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,5 | 1.44 ng/mL | Geometric Coefficient of Variation 16.6 |
| Empa + Ramipril | Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,2 | 1.02 ng/mL | Geometric Coefficient of Variation 21.7 |
| Empa + Ramipril | Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,4 | 1.37 ng/mL | Geometric Coefficient of Variation 17.2 |
| Empa + Ramipril | Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N) | Cpre,3 | 1.31 ng/mL | Geometric Coefficient of Variation 17.4 |
Secondary
Terminal Half-life (T 1/2,ss)
Terminal half-life of the analyte in plasma at steady-state.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa Alone | Terminal Half-life (T 1/2,ss) | Total empa | 12.7 hours | Geometric Coefficient of Variation 37.9 |
| Empa Alone | Terminal Half-life (T 1/2,ss) | Total ramipril | NA hours | — |
| Empa Alone | Terminal Half-life (T 1/2,ss) | Total ramiprilat | NA hours | — |
| Empa + Ramipril | Terminal Half-life (T 1/2,ss) | Total ramipril | 2.66 hours | Geometric Coefficient of Variation 107 |
| Empa + Ramipril | Terminal Half-life (T 1/2,ss) | Total empa | NA hours | — |
| Empa + Ramipril | Terminal Half-life (T 1/2,ss) | Total ramiprilat | 73.2 hours | Geometric Coefficient of Variation 24.1 |
| Empa + Ramipril | Terminal Half-life (T 1/2,ss) | Total ramipril | 2.32 hours | Geometric Coefficient of Variation 118 |
| Empa + Ramipril | Terminal Half-life (T 1/2,ss) | Total ramiprilat | 76.2 hours | Geometric Coefficient of Variation 32.2 |
| Empa + Ramipril | Terminal Half-life (T 1/2,ss) | Total empa | 13.9 hours | Geometric Coefficient of Variation 37.7 |
Secondary
Terminal Rate Constant (λz,ss)
Terminal rate constant in plasma at steady-state
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa Alone | Terminal Rate Constant (λz,ss) | Total ramipril | NA 1/h | — |
| Empa Alone | Terminal Rate Constant (λz,ss) | Total empa | 0.055 1/h | Geometric Coefficient of Variation 37.9 |
| Empa Alone | Terminal Rate Constant (λz,ss) | Total ramiprilat | NA 1/h | — |
| Empa + Ramipril | Terminal Rate Constant (λz,ss) | Total ramipril | 0.261 1/h | Geometric Coefficient of Variation 107 |
| Empa + Ramipril | Terminal Rate Constant (λz,ss) | Total empa | NA 1/h | — |
| Empa + Ramipril | Terminal Rate Constant (λz,ss) | Total ramiprilat | 0.0095 1/h | Geometric Coefficient of Variation 24.1 |
| Empa + Ramipril | Terminal Rate Constant (λz,ss) | Total empa | 0.050 1/h | Geometric Coefficient of Variation 37.7 |
| Empa + Ramipril | Terminal Rate Constant (λz,ss) | Total ramiprilat | 0.0091 1/h | Geometric Coefficient of Variation 32.2 |
| Empa + Ramipril | Terminal Rate Constant (λz,ss) | Total ramipril | 0.298 1/h | Geometric Coefficient of Variation 118 |
Secondary
Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss)
Time from last dosing to the maximum measured concentration of the analyte in plasma at steady state.
Time frame: 0 hours (h), 20 minutes (min), 40 min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after drug administration on day 5. In addition pre-dose samples, 5 minutes predose, were collected on days 1 to 4
Population: Pharmacokinetic (PK) set: All subjects who took at least one dose of investigational treatment and provided at least one observation for at least one primary endpoint without important protocol violations relevant to the PK evaluation.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Empa Alone | Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Total empa | 1.02 hours | Full Range 42.6 |
| Empa Alone | Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Total ramiprilat | NA hours | — |
| Empa Alone | Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Total ramipril | NA hours | — |
| Empa + Ramipril | Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Total ramipril | 0.333 hours | Full Range 36.4 |
| Empa + Ramipril | Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Total ramiprilat | 2.00 hours | Full Range 23.8 |
| Empa + Ramipril | Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Total empa | NA hours | — |
| Empa + Ramipril | Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Total ramiprilat | 2.00 hours | Full Range 29.4 |
| Empa + Ramipril | Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Total empa | 1.50 hours | Full Range 44.7 |
| Empa + Ramipril | Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss) | Total ramipril | 0.333 hours | Full Range 39.1 |