Healthy, Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
This clinical trial is intended to investigate a possible effect of the CYP 2C9 inhibitor fluconazole on the bioavailability of olodaterol
Interventions
DRUGBI 1744
10 mcg solution for oral inhalation
DRUGFluconazole
400 mg capsule
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_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 6 Hours at Steady State (AUC0-6,ss) | Day 8 of period 1 and day 14 of period 2 | AUC0-6,ss represents the area under the concentration curve of olodaterol in plasma from 0 to time t=6 hours 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 (a metabolite of olodaterol) 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 excreted in urine from 0 to time t=24 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 12 Hours at Steady State (AUC0-12,ss) | Day 8 of period 1 and day 14 of period 2 | AUC0-12,ss represents the area under the concentration curve of olodaterol glucuronide in plasma from 0 to time t=12 at steady state, where t is defined as the latest timepoint 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 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. 35 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 capsule Fluconazole 400 milligram once daily, both for 14 days (with a loading dose of 800 milligram on the first day). | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment Period 1 | Withdrawal by Subject | 1 |
| Treatment Period 2 | Adverse Event | 1 |
| Treatment Period 2 | Other reason not defined above | 1 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 32.0 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 35 | 18 / 34 |
| serious Total, serious adverse events | 0 / 35 | 0 / 34 |
Outcome results
Primary
Area Under Curve From 0 to 6 Hours at Steady State (AUC0-6,ss)
AUC0-6,ss represents the area under the concentration curve of olodaterol in plasma from 0 to time t=6 hours 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 6 Hours at Steady State (AUC0-6,ss) | 19.659 Picogram*hours/milliliter | Geometric Coefficient of Variation 13.6 |
| Olodaterol Plus Fluconazole | Area Under Curve From 0 to 6 Hours at Steady State (AUC0-6,ss) | 22.271 Picogram*hours/milliliter | Geometric Coefficient of Variation 13.6 |
Comparison: Ratio Olodaterol plus Fluconazole and Olodaterolp-value: 0.010190% CI: [105.893, 121.197]ANOVA
Primary
Maximum Concentration at Steady State (Cmax,ss)
Cmax,ss represents the maximum concentration of olodaterol and olodaterol glucuronide (a metabolite of olodaterol) 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
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Olodaterol | Maximum Concentration at Steady State (Cmax,ss) | Olodaterol (N=30;32) | 5.336 Picogram/milliliter | Geometric Coefficient of Variation 15.5 |
| Olodaterol | Maximum Concentration at Steady State (Cmax,ss) | Olodaterol glucuronide (N=33;32) | 4.211 Picogram/milliliter | Geometric Coefficient of Variation 19.4 |
| Olodaterol Plus Fluconazole | Maximum Concentration at Steady State (Cmax,ss) | Olodaterol (N=30;32) | 5.805 Picogram/milliliter | Geometric Coefficient of Variation 15.5 |
| Olodaterol Plus Fluconazole | Maximum Concentration at Steady State (Cmax,ss) | Olodaterol glucuronide (N=33;32) | 3.621 Picogram/milliliter | Geometric Coefficient of Variation 19.4 |
Comparison: Ratio Olodaterol plus Fluconazole and Olodaterol for the category Olodaterolp-value: 0.000990% CI: [101.59, 116.487]ANOVA
Comparison: Ratio Olodaterol plus Fluconazole and Olodaterol for the category Olodaterol glucuronidep-value: 0.071190% CI: [79.277, 93.253]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 excreted in urine from 0 to time t=24 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
| 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 | 563.459 ng | Geometric Coefficient of Variation 33.5 |
| Olodaterol | Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss) | Olodaterol glucuronide | 465.946 ng | Geometric Coefficient of Variation 26.5 |
| Olodaterol Plus Fluconazole | Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss) | Olodaterol | 647.004 ng | Geometric Coefficient of Variation 33.5 |
| Olodaterol Plus Fluconazole | Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss) | Olodaterol glucuronide | 347.030 ng | Geometric Coefficient of Variation 26.5 |
Comparison: Ratio Olodaterol plus Fluconazole and Olodaterol for the category Olodaterolp-value: 0.153990% CI: [99.94, 131.932]ANOVA
Comparison: Ratio Olodaterol plus Fluconazole and Olodaterol for the category Olodaterol glucuronidep-value: 0.857490% CI: [66.619, 83.266]ANOVA
Secondary
Area Under Curve From 0 to 12 Hours at Steady State (AUC0-12,ss)
AUC0-12,ss represents the area under the concentration curve of olodaterol glucuronide in plasma from 0 to time t=12 at steady state, where t is defined as the latest timepoint 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
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol | Area Under Curve From 0 to 12 Hours at Steady State (AUC0-12,ss) | 33.389 Picogram*hours/milliliter | Geometric Coefficient of Variation 14.6 |
| Olodaterol Plus Fluconazole | Area Under Curve From 0 to 12 Hours at Steady State (AUC0-12,ss) | 24.735 Picogram*hours/milliliter | Geometric Coefficient of Variation 14.6 |
Comparison: Ratio Olodaterol plus Fluconazole and Olodaterolp-value: 0.964690% CI: [69.105, 79.418]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 | 35 participants |
| Olodaterol Plus Fluconazole | Assessment of Tolerability by the Investigator | Not assessable | 0 participants |
| Olodaterol Plus Fluconazole | Assessment of Tolerability by the Investigator | Good | 30 participants |
| Olodaterol Plus Fluconazole | Assessment of Tolerability by the Investigator | Satisfactory | 3 participants |
| Olodaterol Plus Fluconazole | Assessment of Tolerability by the Investigator | Not satisfactory | 0 participants |
| Olodaterol Plus Fluconazole | Assessment of Tolerability by the Investigator | Bad | 1 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 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 had taken at least 1 dose of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olodaterol | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | 0 participants |
| Olodaterol Plus Fluconazole | 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
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olodaterol | Fraction of Urine Excretion From 0 to 24 Hours at Steady State (fe0-24,ss) | 5.63 percentage of olodaterol | Geometric Coefficient of Variation 39.8 |
| Olodaterol Plus Fluconazole | Fraction of Urine Excretion From 0 to 24 Hours at Steady State (fe0-24,ss) | 6.45 percentage of olodaterol | Geometric Coefficient of Variation 33.1 |
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
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Olodaterol | Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) | Olodaterol glucuronide (N=33;32) | 2.00 Hours |
| Olodaterol | Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) | Olodaterol (N=30;32) | 0.250 Hours |
| Olodaterol Plus Fluconazole | Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) | Olodaterol (N=30;32) | 0.250 Hours |
| Olodaterol Plus Fluconazole | Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) | Olodaterol glucuronide (N=33;32) | 2.03 Hours |