Trial Outcomes & Findings for Relative Bioavailability of Empagliflozin (BI 10773) and Ramipril Administered Together Compared to Empagliflozin (BI 10773) and Ramipril Alone in Healthy Volunteers (NCT NCT01284621)
NCT ID: NCT01284621
Last Updated: 2014-07-22
Results Overview
Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of empagliflozin (empa).
COMPLETED
PHASE1
23 participants
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
2014-07-22
Participant Flow
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.
Participant milestones
| Measure |
Empa Alone / Empa + Ramipril / Ramipril Alone
Patients were administered three treatments in the following order:
* Empagliflozin alone
* Empagliflozin plus Ramipril
* Ramipril
|
Empa Alone / Ramipril Alone / Empa + Ramipril
Patients were administered three treatments in the following order:
* Empagliflozin alone
* Ramipril
* Empagliflozin plus Ramipril
|
Ramipril Alone / Empa Alone / Empa + Ramipril
Patients were administered three treatments in the following order:
* Ramipril
* Empagliflozin alone
* Empagliflozin plus Ramipril
|
Ramipril Alone / Empa + Ramipril / Empa Alone
Patients were administered three treatments in the following order:
* Ramipril
* Empagliflozin plus Ramipril
* Empagliflozin alone
|
Empa + Ramipril / Empa Alone / Ramipril Alone
Patients were administered three treatments in the following order:
* Empagliflozin plus Ramipril
* Empagliflozin alone
* Ramipril
|
Empa + Ramipril / Ramipril Alone / Empa Alone
Patients were administered three treatments in the following order:
* Empagliflozin plus Ramipril
* Ramipril
* Empagliflozin alone
|
|---|---|---|---|---|---|---|
|
First Intervention (8 Days)
STARTED
|
3
|
4
|
4
|
4
|
4
|
4
|
|
First Intervention (8 Days)
COMPLETED
|
3
|
4
|
4
|
4
|
4
|
4
|
|
First Intervention (8 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Washout Period 1 (7 Days)
STARTED
|
3
|
4
|
4
|
4
|
4
|
4
|
|
Washout Period 1 (7 Days)
COMPLETED
|
3
|
4
|
4
|
4
|
3
|
4
|
|
Washout Period 1 (7 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
1
|
0
|
|
Second Intervention (8 Days)
STARTED
|
3
|
4
|
4
|
4
|
3
|
4
|
|
Second Intervention (8 Days)
COMPLETED
|
3
|
4
|
4
|
4
|
3
|
4
|
|
Second Intervention (8 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Washout Period 2 (7 Days)
STARTED
|
3
|
4
|
4
|
4
|
3
|
4
|
|
Washout Period 2 (7 Days)
COMPLETED
|
3
|
4
|
4
|
4
|
3
|
4
|
|
Washout Period 2 (7 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Third Intervention (8 Days)
STARTED
|
3
|
4
|
4
|
4
|
3
|
4
|
|
Third Intervention (8 Days)
COMPLETED
|
3
|
4
|
4
|
4
|
3
|
4
|
|
Third Intervention (8 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
0
|
Reasons for withdrawal
| Measure |
Empa Alone / Empa + Ramipril / Ramipril Alone
Patients were administered three treatments in the following order:
* Empagliflozin alone
* Empagliflozin plus Ramipril
* Ramipril
|
Empa Alone / Ramipril Alone / Empa + Ramipril
Patients were administered three treatments in the following order:
* Empagliflozin alone
* Ramipril
* Empagliflozin plus Ramipril
|
Ramipril Alone / Empa Alone / Empa + Ramipril
Patients were administered three treatments in the following order:
* Ramipril
* Empagliflozin alone
* Empagliflozin plus Ramipril
|
Ramipril Alone / Empa + Ramipril / Empa Alone
Patients were administered three treatments in the following order:
* Ramipril
* Empagliflozin plus Ramipril
* Empagliflozin alone
|
Empa + Ramipril / Empa Alone / Ramipril Alone
Patients were administered three treatments in the following order:
* Empagliflozin plus Ramipril
* Empagliflozin alone
* Ramipril
|
Empa + Ramipril / Ramipril Alone / Empa Alone
Patients were administered three treatments in the following order:
* Empagliflozin plus Ramipril
* Ramipril
* Empagliflozin alone
|
|---|---|---|---|---|---|---|
|
Washout Period 1 (7 Days)
Required unexpected medical treatment
|
0
|
0
|
0
|
0
|
1
|
0
|
Baseline Characteristics
Relative Bioavailability of Empagliflozin (BI 10773) and Ramipril Administered Together Compared to Empagliflozin (BI 10773) and Ramipril Alone in Healthy Volunteers
Baseline characteristics by cohort
| Measure |
Study Overall
n=23 Participants
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.
|
|---|---|
|
Age, Continuous
|
38.0 years
STANDARD_DEVIATION 11.3 • n=5 Participants
|
|
Sex: Female, Male
Female
|
15 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
8 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 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 4Population: 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.
Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of empagliflozin (empa).
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
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
|
5680 nmol*h/L
Geometric Coefficient of Variation 16.3
|
—
|
PRIMARY outcome
Timeframe: 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 4Population: 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.
Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of empagliflozin (empa).
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Total Empa: Maximum Measured Concentration (Cmax,ss)
|
874 nmol/L
Geometric Coefficient of Variation 25.9
|
911 nmol/L
Geometric Coefficient of Variation 21.1
|
—
|
PRIMARY outcome
Timeframe: 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 4Population: 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.
Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ, of ramipril.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
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 37.0
|
7.27 ng*h/mL
Geometric Coefficient of Variation 37.8
|
—
|
PRIMARY outcome
Timeframe: 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 4Population: 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.
Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramipril.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Total Ramipril: Maximum Measured Concentration (Cmax,ss)
|
8.42 ng/mL
Geometric Coefficient of Variation 45.6
|
8.97 ng/mL
Geometric Coefficient of Variation 53.6
|
—
|
PRIMARY outcome
Timeframe: 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 4Population: 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.
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).
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
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
|
85.1 ng*h/mL
Geometric Coefficient of Variation 20.1
|
—
|
PRIMARY outcome
Timeframe: 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 4Population: 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.
Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval, τ, of ramiprilat.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Total Ramiprilat: Maximum Measured Concentration (Cmax,ss)
|
11.2 ng/mL
Geometric Coefficient of Variation 36.8
|
10.5 ng/mL
Geometric Coefficient of Variation 46.6
|
—
|
SECONDARY outcome
Timeframe: 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 4Population: 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.
Predose concentration of the analyte in plasma prior to administration of the Nth dose, of empagliflozin.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Cpre,3
|
45.8 nmol/L
Geometric Coefficient of Variation 33.7
|
45.1 nmol/L
Geometric Coefficient of Variation 30.6
|
—
|
|
Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Cpre,2
|
40.3 nmol/L
Geometric Coefficient of Variation 31.0
|
38.6 nmol/L
Geometric Coefficient of Variation 32.1
|
—
|
|
Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Cpre,4
|
49.2 nmol/L
Geometric Coefficient of Variation 29.5
|
46.4 nmol/L
Geometric Coefficient of Variation 27.2
|
—
|
|
Empa: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Cpre,5
|
47.8 nmol/L
Geometric Coefficient of Variation 25.5
|
48.3 nmol/L
Geometric Coefficient of Variation 27.9
|
—
|
SECONDARY outcome
Timeframe: 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 4Population: 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.
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.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Cpre,2
|
1.03 ng/mL
Geometric Coefficient of Variation 25.5
|
1.02 ng/mL
Geometric Coefficient of Variation 21.7
|
—
|
|
Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Cpre,3
|
1.33 ng/mL
Geometric Coefficient of Variation 21.9
|
1.31 ng/mL
Geometric Coefficient of Variation 17.4
|
—
|
|
Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Cpre,4
|
1.39 ng/mL
Geometric Coefficient of Variation 20.7
|
1.37 ng/mL
Geometric Coefficient of Variation 17.2
|
—
|
|
Ramiprilat: Predose Concentration Prior to Administration of the Nth Dose (Cpre,N)
Cpre,5
|
1.45 ng/mL
Geometric Coefficient of Variation 23.4
|
1.44 ng/mL
Geometric Coefficient of Variation 16.6
|
—
|
SECONDARY outcome
Timeframe: 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 4Population: 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.
Time from last dosing to the maximum measured concentration of the analyte in plasma at steady state.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss)
Total empa
|
1.02 hours
Full Range 42.6 • Interval 0.667 to 3.0
|
NA hours
Full Range NA
Not applicable - no ramipril in this treatment arm
|
1.50 hours
Full Range 44.7 • Interval 1.0 to 4.0
|
|
Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss)
Total ramipril
|
NA hours
Full Range NA
Not applicable - no empagliflozin in this treatment arm
|
0.333 hours
Full Range 36.4 • Interval 0.333 to 1.0
|
0.333 hours
Full Range 39.1 • Interval 0.333 to 1.0
|
|
Time From Last Dosing to the Maximum Measured Concentration (Tmax,ss)
Total ramiprilat
|
NA hours
Full Range NA
Not applicable - no empagliflozin in this treatment arm
|
2.00 hours
Full Range 23.8 • Interval 1.48 to 4.02
|
2.00 hours
Full Range 29.4 • Interval 1.5 to 4.0
|
SECONDARY outcome
Timeframe: 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 4Population: 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.
Terminal rate constant in plasma at steady-state
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Terminal Rate Constant (λz,ss)
Total empa
|
0.055 1/h
Geometric Coefficient of Variation 37.9
|
NA 1/h
Geometric Coefficient of Variation NA
Not applicable - no ramipril in this treatment arm
|
0.050 1/h
Geometric Coefficient of Variation 37.7
|
|
Terminal Rate Constant (λz,ss)
Total ramipril
|
NA 1/h
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
0.261 1/h
Geometric Coefficient of Variation 107
|
0.298 1/h
Geometric Coefficient of Variation 118
|
|
Terminal Rate Constant (λz,ss)
Total ramiprilat
|
NA 1/h
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
0.0095 1/h
Geometric Coefficient of Variation 24.1
|
0.0091 1/h
Geometric Coefficient of Variation 32.2
|
SECONDARY outcome
Timeframe: 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 4Population: 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.
Terminal half-life of the analyte in plasma at steady-state.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Terminal Half-life (T 1/2,ss)
Total ramiprilat
|
NA hours
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
73.2 hours
Geometric Coefficient of Variation 24.1
|
76.2 hours
Geometric Coefficient of Variation 32.2
|
|
Terminal Half-life (T 1/2,ss)
Total empa
|
12.7 hours
Geometric Coefficient of Variation 37.9
|
NA hours
Geometric Coefficient of Variation NA
Not applicable - no ramipril in this treatment arm
|
13.9 hours
Geometric Coefficient of Variation 37.7
|
|
Terminal Half-life (T 1/2,ss)
Total ramipril
|
NA hours
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
2.66 hours
Geometric Coefficient of Variation 107
|
2.32 hours
Geometric Coefficient of Variation 118
|
SECONDARY outcome
Timeframe: 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 4Population: 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.
Mean residence time of the analyte in the body after oral administration at steady-state.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Mean Residence Time (MRTpo,ss)
Total empa
|
9.95 hours
Geometric Coefficient of Variation 18.0
|
NA hours
Geometric Coefficient of Variation NA
Not applicable - no ramipril in this treatment arm
|
9.68 hours
Geometric Coefficient of Variation 16.8
|
|
Mean Residence Time (MRTpo,ss)
Total ramipril
|
NA hours
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
1.29 hours
Geometric Coefficient of Variation 54.2
|
1.42 hours
Geometric Coefficient of Variation 57.8
|
|
Mean Residence Time (MRTpo,ss)
Total ramiprilat
|
NA hours
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
44.7 hours
Geometric Coefficient of Variation 29.9
|
47.1 hours
Geometric Coefficient of Variation 38.7
|
SECONDARY outcome
Timeframe: 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 4Population: 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.
Apparent clearance of the analyte in plasma after extravascular administration at steady-state.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Apparent Clearance After Extravascular Administration (CL/Fss)
Total ramiprilat
|
NA mL/min
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
955 mL/min
Geometric Coefficient of Variation 15.5
|
979 mL/min
Geometric Coefficient of Variation 20.1
|
|
Apparent Clearance After Extravascular Administration (CL/Fss)
Total empa
|
158 mL/min
Geometric Coefficient of Variation 18.1
|
NA mL/min
Geometric Coefficient of Variation NA
Not applicable - no ramipril in this treatment arm
|
163 mL/min
Geometric Coefficient of Variation 16.3
|
|
Apparent Clearance After Extravascular Administration (CL/Fss)
Total ramipril
|
NA mL/min
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
12600 mL/min
Geometric Coefficient of Variation 37.0
|
11500 mL/min
Geometric Coefficient of Variation 37.8
|
SECONDARY outcome
Timeframe: 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 4Population: 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.
Apparent volume of distribution at steady-state during the terminal phase λz following an extravascular dose.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Apparent Volume of Distribution During the Terminal Phase (Vz/Fss)
Total empa
|
174 L
Geometric Coefficient of Variation 31.8
|
NA L
Geometric Coefficient of Variation NA
Not applicable - no ramipril in this treatment arm
|
196 L
Geometric Coefficient of Variation 40.0
|
|
Apparent Volume of Distribution During the Terminal Phase (Vz/Fss)
Total ramipril
|
NA L
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
2910 L
Geometric Coefficient of Variation 89.1
|
2310 L
Geometric Coefficient of Variation 97.3
|
|
Apparent Volume of Distribution During the Terminal Phase (Vz/Fss)
Total ramiprilat
|
NA L
Geometric Coefficient of Variation NA
Not applicable - no empagliflozin in this treatment arm
|
6050 L
Geometric Coefficient of Variation 32.0
|
6460 L
Geometric Coefficient of Variation 42.5
|
SECONDARY outcome
Timeframe: 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.
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.
Outcome measures
| Measure |
Empa Alone
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Empa + Ramipril
n=22 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
n=23 Participants
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Blood Chemistry and Tolerability
|
0 participants
|
0 participants
|
0 participants
|
Adverse Events
Empa Alone
Ramipril Alone
Empa + Ramipril
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Empa Alone
n=22 participants at risk
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5.
|
Ramipril Alone
n=22 participants at risk
A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
Empa + Ramipril
n=23 participants at risk
Empagliflozin 25mg (Empa) was administered once daily from day 1 to day 5. A single dose of ramipril 2.5mg was administered on day 1. Ramipril 5mg was administered once daily from day 2 to day 5.
|
|---|---|---|---|
|
Gastrointestinal disorders
Nausea
|
0.00%
0/22 • Treatment duration plus following washout period (36 days)
|
0.00%
0/22 • Treatment duration plus following washout period (36 days)
|
8.7%
2/23 • Treatment duration plus following washout period (36 days)
|
|
Nervous system disorders
Headache
|
4.5%
1/22 • Treatment duration plus following washout period (36 days)
|
13.6%
3/22 • Treatment duration plus following washout period (36 days)
|
0.00%
0/22 • Treatment duration plus following washout period (36 days)
|
Additional Information
Boehringer Ingelheim Call Center
Boehringer Ingelheim Pharmaceuticals
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place