Healthy
Conditions
Brief summary
To investigate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of single rising doses of BI 691751 in healthy male subjects (part I). To investigate the relative bioavailability of BI 691751 given as tablet versus oral solution (part II)
Interventions
DRUGBI 691751
oral solution BI 691751, dose 6
DRUGPlacebo
placebo solution
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male subjects 2. Subjects must be able to understand and comply with study requirements 3. Age from 18 to 55 years 4. BMI range: from 18.5 to 29.9 kg/m2 5. Known genotype as specified in the study protocol
Exclusion criteria
1\. Any relevant deviation from healthy conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-72h (Part II) | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 48h and 72h after drug administration | AUC0-72h (area under the concentration-time curve of the analyte of BI 691751 in plasma over the time interval from 0 to 72 h) (part II). PPS-BA included all subjects in the TS who were randomised to the BA part, who provided at least one observation for at least one primary endpoint, had no important protocol violations relevant for the statistical evaluation of BA and did not experience emesis at or before twice the median tmax. |
| Cmax (Part II) | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug administration | Cmax (maximum measured concentration of the analyte of BI 691751 in plasma) (part II) |
| Frequency of Subjects With Drug-related Adverse Events (Part I) | Part I: 'Day1 to Day21 for Dose 1, 2,3 &4 and Day1 to Day45 for Dose group 5,6 & 7 | Frequency of subjects with drug-related Adverse Events (AEs) (Part I) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| t1/2 (Part I) | for dose 1 & 2: up to 168 hours (h), for dose 3 & 4: up to 240h, for dose 5 to 8: up to 720h | t1/2 (terminal half-life of the analyte of BI 691751 in plasma) (part I) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin |
| Cmax (Part I) | for dose 1 & 2: up to 168h, for dose 3 & 4: up to 240h, for dose 5 to 8: up to 720h | Cmax (maximum measured concentration of BI 691751 in plasma) (part I) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin |
| Tmax (Part I) | for dose 1 & 2: up to 168 hours (h), for dose 3 & 4: up to 240h, for dose 5 to 8: up to 720h | tmax (time from dosing to maximum measured concentration of BI 691751) (part I) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin |
| AUC0-infinity (Part I) | for dose 1 & 2: up to 168 hours (h), for dose 3 & 4: up to 240h, for dose 5 to 8: up to 720h | AUC0-infinity (area under the concentration-time curve of BI 691751 in plasma over the time interval from 0 extrapolated to infinity) (part I) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin |
| AUC0-tz | Part 1: for dose 1 & 2: up to 168 hours (h), for dose 3 & 4: up to 240h, for dose 5 to 7: up to 720h; Part 2: up to 720h | AUC0-tz (area under the concentration-time curve of BI 691751 in plasma over the time interval from 0 up to the last quantifiable data point) (Part I and Part II) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Part I) placebo solution
Placebo: placebo solution | 13 |
| BI 691751dose 1 (Part I) single dose given as oral solution
BI 691751: oral solution BI 69175, dose 1 (0.5 mg powder) | 6 |
| BI 691751 Dose 2 (Part I) single dose given as oral solution
BI 691751: oral solution BI 691751, dose 2 (1.5 mg powder) | 5 |
| BI 691751 Dose 3 (Part I) single dose given as oral solution
BI 691751: oral solution BI 691751, dose 3 (5 mg powder) | 6 |
| BI 691751 Dose 4 (Part I) single dose given as oral solution
BI 691751: oral solution BI 69175, dose 4 (15 mg powder) | 6 |
| BI 691751 Dose 5 (Part I) single dose given as oral solution
BI 691751: oral solution BI 691751, dose 5 (30 mg powder) | 6 |
| BI 691751 Dose 6 (Part I) single dose given as oral solution
BI 691751: oral solution BI 691751, dose 6 (60 mg powder) | 5 |
| BI 691751 Dose 7 (Part I) single dose given as oral solution
BI 691751: oral solution BI 691751, dose 7 (90 mg powder) | 5 |
| BI 691751 Tablet (Part II) single dose given as 1 tablet
BI 691751: 1 tablet (10 mg) | 17 |
| BI 691751 Solution (Part II); Extensive Metabolizers single dose given as oral solution BI 691751: oral solution (10 mg)
5 subjects had no measurable concentration of BI 691751 because a drug-free solution has been administered by mistake. Therefore their results were excluded from all analyses. | 12 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo (Part I) | BI 691751dose 1 (Part I) | BI 691751 Dose 2 (Part I) | BI 691751 Dose 3 (Part I) | BI 691751 Dose 4 (Part I) | BI 691751 Dose 5 (Part I) | BI 691751 Dose 6 (Part I) | BI 691751 Dose 7 (Part I) | BI 691751 Tablet (Part II) | BI 691751 Solution (Part II); Extensive Metabolizers | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.3 years STANDARD_DEVIATION 8.2 | 31.2 years STANDARD_DEVIATION 8 | 32.0 years STANDARD_DEVIATION 8.4 | 34.5 years STANDARD_DEVIATION 6.8 | 26.5 years STANDARD_DEVIATION 5.2 | 37.5 years STANDARD_DEVIATION 6 | 29.2 years STANDARD_DEVIATION 2.6 | 30.2 years STANDARD_DEVIATION 8 | 32.2 years STANDARD_DEVIATION 9.3 | 35.8 years STANDARD_DEVIATION 10.2 | 31.8 years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 5 Participants | 5 Participants | 17 Participants | 12 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 13 | 1 / 6 | 2 / 5 | 2 / 6 | 2 / 6 | 1 / 6 | 3 / 5 | 4 / 5 | 5 / 17 | 3 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 5 | 0 / 17 | 1 / 12 |
Outcome results
Primary
AUC0-72h (Part II)
AUC0-72h (area under the concentration-time curve of the analyte of BI 691751 in plasma over the time interval from 0 to 72 h) (part II). PPS-BA included all subjects in the TS who were randomised to the BA part, who provided at least one observation for at least one primary endpoint, had no important protocol violations relevant for the statistical evaluation of BA and did not experience emesis at or before twice the median tmax.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 48h and 72h after drug administration
Population: Per protocol set for evaluation of bioavailability (PPS-BA). Only subjects with calculable PK parameter were analysed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 691751 Tablet Extensive Metabolizers (Part II) | AUC0-72h (Part II) | 2740 nmol*h/L | Geometric Coefficient of Variation 26.1 |
| BI 691751 Tablet Poor Metabolizers (Part II) | AUC0-72h (Part II) | 3050 nmol*h/L | Geometric Coefficient of Variation 20.5 |
| BI 691751 Solution (Part II); Extensive Metabolizers | AUC0-72h (Part II) | 2800 nmol*h/L | Geometric Coefficient of Variation 22.2 |
Comparison: Only extensive CYP2D6 metabolisers were selected: 12 (all) subjects of group 'BI 691751 tablet extensive metabolizers (part II)' and 7 (all investigated) subjects of group 'BI 691751 solution (part II) '.90% CI: [79.963, 119.809]ANOVA
Comparison: Comparison of poor metabolisers (5 (all) subjects of group 'BI 691751 tablet poor metabolizers (part II)') and extensive metabolisers (12 (all) subjects of group 'BI 691751 tablet extensive metabolizers (part II)').90% CI: [88.596, 139.576]ANOVA
Primary
Cmax (Part II)
Cmax (maximum measured concentration of the analyte of BI 691751 in plasma) (part II)
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug administration
Population: PPS-BA. Only subjects with calculable PK parameter were analysed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 691751 Tablet Extensive Metabolizers (Part II) | Cmax (Part II) | 223 nmol/L | Geometric Coefficient of Variation 33.6 |
| BI 691751 Tablet Poor Metabolizers (Part II) | Cmax (Part II) | 207 nmol/L | Geometric Coefficient of Variation 31.3 |
| BI 691751 Solution (Part II); Extensive Metabolizers | Cmax (Part II) | 220 nmol/L | Geometric Coefficient of Variation 14.4 |
Comparison: Only extensive CYP2D6 metabolisers were selected: 12 (all) subjects of group 'BI 691751 tablet extensive metabolizers (part II)' and 7 (all investigated) subjects of group 'BI 691751 solution (part II) '.90% CI: [80.593, 127.351]ANOVA
Comparison: Comparison of poor metabolisers (5 (all) subjects of group 'BI 691751 tablet poor metabolizers (part II)') and extensive metabolisers (12 (all) subjects of group 'BI 691751 tablet extensive metabolizers (part II)').90% CI: [68.662, 125.119]ANOVA
Primary
Frequency of Subjects With Drug-related Adverse Events (Part I)
Frequency of subjects with drug-related Adverse Events (AEs) (Part I)
Time frame: Part I: 'Day1 to Day21 for Dose 1, 2,3 &4 and Day1 to Day45 for Dose group 5,6 & 7
Population: Treated Set (TS): all subjects who were documented to have taken at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 691751 Tablet Extensive Metabolizers (Part II) | Frequency of Subjects With Drug-related Adverse Events (Part I) | 1 Participants |
| BI 691751 Tablet Poor Metabolizers (Part II) | Frequency of Subjects With Drug-related Adverse Events (Part I) | 0 Participants |
| BI 691751 Solution (Part II); Extensive Metabolizers | Frequency of Subjects With Drug-related Adverse Events (Part I) | 1 Participants |
| BI 691751 Dose 4 (Part I) | Frequency of Subjects With Drug-related Adverse Events (Part I) | 0 Participants |
| BI 691751 Dose 5 (Part I) | Frequency of Subjects With Drug-related Adverse Events (Part I) | 0 Participants |
| BI 691751 Dose 6 (Part I) | Frequency of Subjects With Drug-related Adverse Events (Part I) | 0 Participants |
| BI 691751 Dose 7 (Part I) | Frequency of Subjects With Drug-related Adverse Events (Part I) | 0 Participants |
| BI 691751 Solution (Part II); Extensive Metabolizers | Frequency of Subjects With Drug-related Adverse Events (Part I) | 1 Participants |
Secondary
AUC0-infinity (Part I)
AUC0-infinity (area under the concentration-time curve of BI 691751 in plasma over the time interval from 0 extrapolated to infinity) (part I) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin
Time frame: for dose 1 & 2: up to 168 hours (h), for dose 3 & 4: up to 240h, for dose 5 to 8: up to 720h
Population: PPS-DP. Only subjects with calculable PK parameter were analysed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 691751 Solution (Part II); Extensive Metabolizers | AUC0-infinity (Part I) | 1140 nmol*h/L | Geometric Coefficient of Variation 34.5 |
| BI 691751 Dose 4 (Part I) | AUC0-infinity (Part I) | 7250 nmol*h/L | Geometric Coefficient of Variation 15.9 |
| BI 691751 Dose 5 (Part I) | AUC0-infinity (Part I) | 11900 nmol*h/L | Geometric Coefficient of Variation 27.2 |
| BI 691751 Dose 6 (Part I) | AUC0-infinity (Part I) | 24500 nmol*h/L | Geometric Coefficient of Variation 20 |
| BI 691751 Dose 7 (Part I) | AUC0-infinity (Part I) | 41000 nmol*h/L | Geometric Coefficient of Variation 26.9 |
| BI 691751 Solution (Part II); Extensive Metabolizers | AUC0-infinity (Part I) | 3630 nmol*h/L | Geometric Coefficient of Variation 28.5 |
Comparison: Dose proportionality of BI 691751 was explored using a power model (regression model applied to log-transformed data).95% CI: [0.8107, 1.1266]Regression, Linear
Secondary
AUC0-tz
AUC0-tz (area under the concentration-time curve of BI 691751 in plasma over the time interval from 0 up to the last quantifiable data point) (Part I and Part II) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin
Time frame: Part 1: for dose 1 & 2: up to 168 hours (h), for dose 3 & 4: up to 240h, for dose 5 to 7: up to 720h; Part 2: up to 720h
Population: PPS-DP for part I and PPS-BA for part II. Only subjects with calculable PK parameter were analysed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 691751 Tablet Poor Metabolizers (Part II) | AUC0-tz | 29.5 nmol*h/L | Geometric Coefficient of Variation 18.4 |
| BI 691751 Solution (Part II); Extensive Metabolizers | AUC0-tz | 791 nmol*h/L | Geometric Coefficient of Variation 45.4 |
| BI 691751 Dose 4 (Part I) | AUC0-tz | 6310 nmol*h/L | Geometric Coefficient of Variation 15.4 |
| BI 691751 Dose 5 (Part I) | AUC0-tz | 11400 nmol*h/L | Geometric Coefficient of Variation 28.3 |
| BI 691751 Dose 6 (Part I) | AUC0-tz | 24100 nmol*h/L | Geometric Coefficient of Variation 21.1 |
| BI 691751 Dose 7 (Part I) | AUC0-tz | 40500 nmol*h/L | Geometric Coefficient of Variation 27.2 |
| BI 691751 Solution (Part II); Extensive Metabolizers | AUC0-tz | 3150 nmol*h/L | Geometric Coefficient of Variation 32 |
| BI 691751 Tablet Poor Metabolizers (Part II) | AUC0-tz | 3460 nmol*h/L | Geometric Coefficient of Variation 17.4 |
| BI 691751 Solution (Part II); Extensive Metabolizers | AUC0-tz | 3300 nmol*h/L | Geometric Coefficient of Variation 28.5 |
Comparison: Only extensive CYP2D6 metabolisers were selected: 12 (all) subjects of group 'BI 691751 tablet extensive metabolizers (part II)' and 7 (all investigated) subjects of group 'BI 691751 solution (part II) '.90% CI: [74.414, 122.511]ANOVA
Comparison: Comparison of poor metabolisers (5 (all) subjects of group 'BI 691751 tablet poor metabolizers (part II)') and extensive metabolisers (12 (all) subjects of group 'BI 691751 tablet extensive metabolizers (part II)').90% CI: [84.376, 142.894]ANOVA
95% CI: [0.833, 1.179]Regression, Linear
Secondary
Cmax (Part I)
Cmax (maximum measured concentration of BI 691751 in plasma) (part I) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin
Time frame: for dose 1 & 2: up to 168h, for dose 3 & 4: up to 240h, for dose 5 to 8: up to 720h
Population: Per protocol set for evaluation of dose proportionality (PPS-DP): This subject set includes all subjects of the TS who were randomised to active treatment in the single rising dose part or BA part, and had no important PVs relevant for the statistical evaluation of dose proportionality. Only subjects with calculable PK parameter were analysed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 691751 Tablet Extensive Metabolizers (Part II) | Cmax (Part I) | 3.45 nmol/L | Geometric Coefficient of Variation 15.5 |
| BI 691751 Tablet Poor Metabolizers (Part II) | Cmax (Part I) | 18.3 nmol/L | Geometric Coefficient of Variation 39.3 |
| BI 691751 Solution (Part II); Extensive Metabolizers | Cmax (Part I) | 88.9 nmol/L | Geometric Coefficient of Variation 59.1 |
| BI 691751 Dose 4 (Part I) | Cmax (Part I) | 729 nmol/L | Geometric Coefficient of Variation 21.5 |
| BI 691751 Dose 5 (Part I) | Cmax (Part I) | 1320 nmol/L | Geometric Coefficient of Variation 31.5 |
| BI 691751 Dose 6 (Part I) | Cmax (Part I) | 3320 nmol/L | Geometric Coefficient of Variation 46.7 |
| BI 691751 Dose 7 (Part I) | Cmax (Part I) | 4180 nmol/L | Geometric Coefficient of Variation 22.2 |
| BI 691751 Solution (Part II); Extensive Metabolizers | Cmax (Part I) | 220 nmol/L | Geometric Coefficient of Variation 14.4 |
95% CI: [0.8265, 1.2201]Regression, Linear
Secondary
t1/2 (Part I)
t1/2 (terminal half-life of the analyte of BI 691751 in plasma) (part I) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin
Time frame: for dose 1 & 2: up to 168 hours (h), for dose 3 & 4: up to 240h, for dose 5 to 8: up to 720h
Population: Pharmacokinetic (PK) set (PKS) which includes all subjects of the treated set were were randomised to active treatment in the single rising dose part of bioavailability part, and had no important protocol violations relevant for the statistical evaluation of further PK parameters. Only subjects with calculable PK parameter were analysed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 691751 Solution (Part II); Extensive Metabolizers | t1/2 (Part I) | 65.4 h | Geometric Coefficient of Variation 37.8 |
| BI 691751 Dose 4 (Part I) | t1/2 (Part I) | 97.4 h | Geometric Coefficient of Variation 63.3 |
| BI 691751 Dose 5 (Part I) | t1/2 (Part I) | 74.9 h | Geometric Coefficient of Variation 49.2 |
| BI 691751 Dose 6 (Part I) | t1/2 (Part I) | 57.2 h | Geometric Coefficient of Variation 34.3 |
| BI 691751 Dose 7 (Part I) | t1/2 (Part I) | 78.3 h | Geometric Coefficient of Variation 16.9 |
| BI 691751 Solution (Part II); Extensive Metabolizers | t1/2 (Part I) | 59.4 h | Geometric Coefficient of Variation 57.1 |
Secondary
Tmax (Part I)
tmax (time from dosing to maximum measured concentration of BI 691751) (part I) Time frame: Dose 1 and 2: 1 hour (h) before drug administration (admin) and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h and 168h after drug admin Dose 3 and 4: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h (dose group 4 only), 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h and 240h after drug admin Dose 5 to 7: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 336h, 432h, 528h, 624h and 720h after drug admin Dose 8: 1h before drug admin and 20 min, 40min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 216h, 384h, 552h and 720h after drug admin
Time frame: for dose 1 & 2: up to 168 hours (h), for dose 3 & 4: up to 240h, for dose 5 to 8: up to 720h
Population: PKS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 691751 Tablet Extensive Metabolizers (Part II) | Tmax (Part I) | 0.667 h |
| BI 691751 Tablet Poor Metabolizers (Part II) | Tmax (Part I) | 0.667 h |
| BI 691751 Solution (Part II); Extensive Metabolizers | Tmax (Part I) | 0.842 h |
| BI 691751 Dose 4 (Part I) | Tmax (Part I) | 0.500 h |
| BI 691751 Dose 5 (Part I) | Tmax (Part I) | 0.350 h |
| BI 691751 Dose 6 (Part I) | Tmax (Part I) | 0.667 h |
| BI 691751 Dose 7 (Part I) | Tmax (Part I) | 0.667 h |
| BI 691751 Solution (Part II); Extensive Metabolizers | Tmax (Part I) | 0.667 h |