Healthy, Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
This clinical trial is intended to investigate a possible effect of the p-gp inhibitor ketoconazole on the bioavailability of olodaterol
Interventions
DRUGBI 1744
10 mcg solution for oral inhalation
DRUGKetoconazole
400 mg tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy male and female volunteers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Curve From 0 to 1 Hour at Steady State (AUC0-1,ss) | Day 8 of period 1 and day 14 of period 2 | AUC0-1,ss represents the area under the concentration curve of olodaterol in plasma from 0 to time t=1 hour at steady state, where t is defined as the latest time-point where at least 2/3 of the subjects in both treatment periods reveal quantifiable plasma concentrations of olodaterol. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV. |
| Maximum Concentration at Steady State (Cmax,ss) | Day 8 of period 1 and day 14 of period 2 | Cmax,ss represents the maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss) | Day 8 of period 1 and day 14 of period 2 | Ae0-24,ss represents the amount of olodaterol and olodaterol glucuronide that is eliminated in urine from the time 0 to 24h after administration at steady state. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV. |
| Area Under Curve From 0 to 8 Hours at Steady State (AUC0-8,ss) | Day 8 of period 1 and day 14 of period 2 | AUC0-8,ss represents the area under the concentration curve of olodaterol glucuronide in plasma from 0 to time t=8 at steady state, where t is defined as the latest time-point where at least 2/3 of the subjects in both treatment periods reveal quantifiable plasma concentrations of the analyte. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV. |
| Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) | Day 8 of period 1 and day 14 of period 2 | tmax,ss represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state. |
| Assessment of Tolerability by the Investigator | End of period 1 and end of period 2 | The investigator assessed tolerability based on adverse events and the laboratory evaluation at the end-of-trial examination. The investigator classified the overall tolerability according to the categories 'good', 'satisfactory', 'not satisfactory', and 'bad'. |
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | First administration of trial medication until 6 days after last administration of trial medication | Clinical relevant abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as treatment-induced Adverse Events. |
| Fraction of Urine Excretion From 0 to 24 Hours at Steady State (fe0-24,ss) | Day 8 of period 1 and day 14 of period 2 | fe0-24,ss represents the fraction of olodaterol eliminated in urine from time point 0 to 24 hours after administration at steady state. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Total number of patients treated in the study. This was an open-label, fixed sequence, phase I trial in healthy volunteers. 32 subjects received in period 1 Olodaterol 10 microgram delivered by Respimat inhaler once daily for 8 days and in period 2 Olodaterol 10 microgram delivered by Respimat inhaler once daily plus 1 tablet Ketoconazole 400mg once daily, both for 14 days. | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 38.5 years STANDARD_DEVIATION 7.2 |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 32 | 9 / 32 |
| serious Total, serious adverse events | 0 / 32 | 0 / 32 |
Outcome results
Primary
Area Under Curve From 0 to 1 Hour at Steady State (AUC0-1,ss)
AUC0-1,ss represents the area under the concentration curve of olodaterol in plasma from 0 to time t=1 hour at steady state, where t is defined as the latest time-point where at least 2/3 of the subjects in both treatment periods reveal quantifiable plasma concentrations of olodaterol. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.
Time frame: Day 8 of period 1 and day 14 of period 2
Population: Pharmacokinetic (PK) analysis set includes all evaluable subjects in the treated set providing at least 1 observation for at least 1 PK endpoint without important protocol violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol | Area Under Curve From 0 to 1 Hour at Steady State (AUC0-1,ss) | 2.512 Picogram*hours/milliliter | Geometric Coefficient of Variation 16.4 |
| Olodaterol Plus Ketoconazole | Area Under Curve From 0 to 1 Hour at Steady State (AUC0-1,ss) | 4.231 Picogram*hours/milliliter | Geometric Coefficient of Variation 16.4 |
Comparison: Ratio Olodaterol plus Ketoconazole and Olodaterolp-value: 190% CI: [155.5, 182.4]ANOVA
Primary
Maximum Concentration at Steady State (Cmax,ss)
Cmax,ss represents the maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.
Time frame: Day 8 of period 1 and day 14 of period 2
Population: PK analysis set with evaluable data for this endpoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Olodaterol | Maximum Concentration at Steady State (Cmax,ss) | Olodaterol (N=26;31) | 3.113 Picogram/milliliter | Geometric Coefficient of Variation 16.8 |
| Olodaterol | Maximum Concentration at Steady State (Cmax,ss) | Olodaterol glucuronide (N=32;32) | 5.125 Picogram/milliliter | Geometric Coefficient of Variation 14.7 |
| Olodaterol Plus Ketoconazole | Maximum Concentration at Steady State (Cmax,ss) | Olodaterol (N=26;31) | 5.169 Picogram/milliliter | Geometric Coefficient of Variation 16.8 |
| Olodaterol Plus Ketoconazole | Maximum Concentration at Steady State (Cmax,ss) | Olodaterol glucuronide (N=32;32) | 5.465 Picogram/milliliter | Geometric Coefficient of Variation 14.7 |
Comparison: Ratio Olodaterol plus Ketoconazole and Olodaterol for the category Olodaterolp-value: 190% CI: [153.6, 179.6]ANOVA
Comparison: Ratio Olodaterol plus Ketoconazole and Olodaterol for the category Olodaterol glucuronidep-value: 0.000190% CI: [100.211, 113.463]ANOVA
Secondary
Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss)
Ae0-24,ss represents the amount of olodaterol and olodaterol glucuronide that is eliminated in urine from the time 0 to 24h after administration at steady state. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.
Time frame: Day 8 of period 1 and day 14 of period 2
Population: PK analysis set with evaluable data for this endpoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Olodaterol | Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss) | Olodaterol | 428.972 ng | Geometric Coefficient of Variation 17.8 |
| Olodaterol | Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss) | Olodaterol glucuronide | 445.266 ng | Geometric Coefficient of Variation 18.9 |
| Olodaterol Plus Ketoconazole | Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss) | Olodaterol | 618.716 ng | Geometric Coefficient of Variation 17.8 |
| Olodaterol Plus Ketoconazole | Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss) | Olodaterol glucuronide | 591.620 ng | Geometric Coefficient of Variation 18.9 |
Comparison: Ratio Olodaterol plus Ketoconazole and Olodaterol for the category Olodaterolp-value: 0.998690% CI: [133.853, 155.417]ANOVA
Comparison: Ratio Olodaterol plus Ketoconazole and Olodaterol for the category Olodaterol glucuronidep-value: 0.899190% CI: [122.732, 143.843]ANOVA
Secondary
Area Under Curve From 0 to 8 Hours at Steady State (AUC0-8,ss)
AUC0-8,ss represents the area under the concentration curve of olodaterol glucuronide in plasma from 0 to time t=8 at steady state, where t is defined as the latest time-point where at least 2/3 of the subjects in both treatment periods reveal quantifiable plasma concentrations of the analyte. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.
Time frame: Day 8 of period 1 and day 14 of period 2
Population: PK analysis set with evaluable data for this endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol | Area Under Curve From 0 to 8 Hours at Steady State (AUC0-8,ss) | 27.868 Picogram*hours/milliliter | Geometric Coefficient of Variation 17.9 |
| Olodaterol Plus Ketoconazole | Area Under Curve From 0 to 8 Hours at Steady State (AUC0-8,ss) | 28.076 Picogram*hours/milliliter | Geometric Coefficient of Variation 17.9 |
Comparison: Ratio Olodaterol plus Ketoconazole and Olodaterolp-value: 0.000190% CI: [92.534, 109.692]ANOVA
Secondary
Assessment of Tolerability by the Investigator
The investigator assessed tolerability based on adverse events and the laboratory evaluation at the end-of-trial examination. The investigator classified the overall tolerability according to the categories 'good', 'satisfactory', 'not satisfactory', and 'bad'.
Time frame: End of period 1 and end of period 2
Population: TS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olodaterol | Assessment of Tolerability by the Investigator | Satisfactory | 0 participants |
| Olodaterol | Assessment of Tolerability by the Investigator | Bad | 0 participants |
| Olodaterol | Assessment of Tolerability by the Investigator | Not satisfactory | 0 participants |
| Olodaterol | Assessment of Tolerability by the Investigator | Not assessable | 0 participants |
| Olodaterol | Assessment of Tolerability by the Investigator | Good | 32 participants |
| Olodaterol Plus Ketoconazole | Assessment of Tolerability by the Investigator | Not assessable | 0 participants |
| Olodaterol Plus Ketoconazole | Assessment of Tolerability by the Investigator | Good | 32 participants |
| Olodaterol Plus Ketoconazole | Assessment of Tolerability by the Investigator | Satisfactory | 0 participants |
| Olodaterol Plus Ketoconazole | Assessment of Tolerability by the Investigator | Not satisfactory | 0 participants |
| Olodaterol Plus Ketoconazole | Assessment of Tolerability by the Investigator | Bad | 0 participants |
Secondary
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
Clinical relevant abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as treatment-induced Adverse Events.
Time frame: First administration of trial medication until 6 days after last administration of trial medication
Population: Treated set (TS) - Treated set includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of investigational treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olodaterol | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | 0 participants |
| Olodaterol Plus Ketoconazole | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | 0 participants |
Secondary
Fraction of Urine Excretion From 0 to 24 Hours at Steady State (fe0-24,ss)
fe0-24,ss represents the fraction of olodaterol eliminated in urine from time point 0 to 24 hours after administration at steady state.
Time frame: Day 8 of period 1 and day 14 of period 2
Population: PK analysis set with evaluable data for this endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol | Fraction of Urine Excretion From 0 to 24 Hours at Steady State (fe0-24,ss) | 4.29 Percentage | Geometric Coefficient of Variation 35.2 |
| Olodaterol Plus Ketoconazole | Fraction of Urine Excretion From 0 to 24 Hours at Steady State (fe0-24,ss) | 6.19 Percentage | Geometric Coefficient of Variation 35.9 |
Secondary
Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss)
tmax,ss represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state.
Time frame: Day 8 of period 1 and day 14 of period 2
Population: PK analysis set with evaluable data for this endpoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Olodaterol | Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) | Olodaterol (N=26;31) | 0.250 Hours |
| Olodaterol | Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) | Olodaterol glucuronide (N=32;32) | 4.00 Hours |
| Olodaterol Plus Ketoconazole | Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) | Olodaterol (N=26;31) | 0.333 Hours |
| Olodaterol Plus Ketoconazole | Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) | Olodaterol glucuronide (N=32;32) | 3.01 Hours |