Trial Outcomes & Findings for Interaction of BI 425809 With Midazolam, Warfarin, Omeprazole and Digoxin (NCT NCT02783040)
NCT ID: NCT02783040
Last Updated: 2026-04-15
Results Overview
Maximum measured concentration of S-warfarin in plasma (Cmax) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2.
COMPLETED
PHASE1
13 participants
Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description.
2026-04-15
Participant Flow
This trial in healthy male subjects applied an open-label, crossover design consisting of 2 treatment periods with a fixed sequence. It assessed the influence of multiple doses of BI 425809 (14 days) on single dose pharmacokinetics (PK) of midazolam, warfarin, omeprazole, and digoxin. Furthermore, the short-term effect of BI 425809 on single dose midazolam PK was investigated.
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participant milestones
| Measure |
Probe Drugs (Reference (R))/BI 425809+Probe Drugs (Test (T))
Treatment Period 1 (administration of reference treatment (R)): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
Treatment Period 2 (administration of test treatment (T)): From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 3 of Treatment Period 2 participants administered a single dose of 2 mg of midazolam. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
Between Treatment Period 1 and Treatment Period 2 were at least 5 days wash-out.
|
|---|---|
|
Period 1: Treatment period 1 (06 days)
STARTED
|
13
|
|
Period 1: Treatment period 1 (06 days)
COMPLETED
|
12
|
|
Period 1: Treatment period 1 (06 days)
NOT COMPLETED
|
1
|
|
Washout Period (05 days)
STARTED
|
12
|
|
Washout Period (05 days)
COMPLETED
|
12
|
|
Washout Period (05 days)
NOT COMPLETED
|
0
|
|
Period 2: Treatment period 2 (15 days)
STARTED
|
12
|
|
Period 2: Treatment period 2 (15 days)
COMPLETED
|
12
|
|
Period 2: Treatment period 2 (15 days)
NOT COMPLETED
|
0
|
Reasons for withdrawal
| Measure |
Probe Drugs (Reference (R))/BI 425809+Probe Drugs (Test (T))
Treatment Period 1 (administration of reference treatment (R)): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
Treatment Period 2 (administration of test treatment (T)): From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 3 of Treatment Period 2 participants administered a single dose of 2 mg of midazolam. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
Between Treatment Period 1 and Treatment Period 2 were at least 5 days wash-out.
|
|---|---|
|
Period 1: Treatment period 1 (06 days)
Adverse Event
|
1
|
Baseline Characteristics
Interaction of BI 425809 With Midazolam, Warfarin, Omeprazole and Digoxin
Baseline characteristics by cohort
| Measure |
Probe Drugs (Reference (R))/BI 425809+Probe Drugs (Test (T))
n=13 Participants
Treatment Period 1 (administration of reference treatment (R)): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
Treatment Period 2 (administration of test treatment (T)): From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 3 of Treatment Period 2 participants administered a single dose of 2 mg of midazolam. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
Between Treatment Period 1 and Treatment Period 2 were at least 5 days wash-out.
|
|---|---|
|
Age, Continuous
|
37.1 Years
STANDARD_DEVIATION 13.1 • n=193 Participants
|
|
Sex: Female, Male
Female
|
0 Participants
n=193 Participants
|
|
Sex: Female, Male
Male
|
13 Participants
n=193 Participants
|
PRIMARY outcome
Timeframe: Within 3 h before and up to 24h after administration of midazolam/probe drug cocktail. For detailed timeframe please see outcome measure description.Population: Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary Pharmacokinetic (PK) endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints.
Area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Short-term BI 425809 (after 3rd dose) plus midazolam": Within 3 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of midazolam on Day 3 of Treatment Period 2. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2.
Outcome measures
| Measure |
Treatment Period 1: Probe Drugs
n=13 Participants
Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
|
Treatment Period 2: Short-term BI 425809 (After 3rd Dose) Plus Midazolam
n=12 Participants
Participants administered from Day 1 to Day 3 of Treatment Period 2 orally once daily 25 mg of BI 425809 with 240 ml of water. Within 1 hour after administration of BI 425809 on Day 3 of Treatment Period 2 participants administered orally a single dose of 2 mg of midazolam with 240 ml of water.
|
Treatment Period 2: BI 425809 Plus Probe Drugs
n=12 Participants
From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water.
|
|---|---|---|---|
|
Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
|
23.5 nanogram (ng)*hour (h)/millilitre (mL)
Geometric Coefficient of Variation 33.4
|
19.0 nanogram (ng)*hour (h)/millilitre (mL)
Geometric Coefficient of Variation 40.8
|
16.0 nanogram (ng)*hour (h)/millilitre (mL)
Geometric Coefficient of Variation 29.3
|
PRIMARY outcome
Timeframe: Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description.Population: Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints.
Area under the concentration-time curve of omeprazole in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2.
Outcome measures
| Measure |
Treatment Period 1: Probe Drugs
n=13 Participants
Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
|
Treatment Period 2: Short-term BI 425809 (After 3rd Dose) Plus Midazolam
n=12 Participants
Participants administered from Day 1 to Day 3 of Treatment Period 2 orally once daily 25 mg of BI 425809 with 240 ml of water. Within 1 hour after administration of BI 425809 on Day 3 of Treatment Period 2 participants administered orally a single dose of 2 mg of midazolam with 240 ml of water.
|
Treatment Period 2: BI 425809 Plus Probe Drugs
From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water.
|
|---|---|---|---|
|
Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
|
483 ng*h/mL
Geometric Coefficient of Variation 128
|
384 ng*h/mL
Geometric Coefficient of Variation 118
|
—
|
PRIMARY outcome
Timeframe: Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description.Population: Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints.
Area under the concentration-time curve of S-warfarin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2.
Outcome measures
| Measure |
Treatment Period 1: Probe Drugs
n=12 Participants
Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
|
Treatment Period 2: Short-term BI 425809 (After 3rd Dose) Plus Midazolam
n=12 Participants
Participants administered from Day 1 to Day 3 of Treatment Period 2 orally once daily 25 mg of BI 425809 with 240 ml of water. Within 1 hour after administration of BI 425809 on Day 3 of Treatment Period 2 participants administered orally a single dose of 2 mg of midazolam with 240 ml of water.
|
Treatment Period 2: BI 425809 Plus Probe Drugs
From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water.
|
|---|---|---|---|
|
Area Under the Concentration-time Curve of S-warfarin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
|
15100 ng*h/mL
Geometric Coefficient of Variation 21.4
|
15200 ng*h/mL
Geometric Coefficient of Variation 22.6
|
—
|
PRIMARY outcome
Timeframe: Blood sampling was done before and up to 95 after administration of digoxin. For detailed timeframe please see outcome measure description.Population: Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints.
Area under the concentration-time curve of digoxin from 0 to the time of the last quantifiable data point (AUC0-tz) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 10 minutes before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 2 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 4 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 11 of Treatment Period 2.
Outcome measures
| Measure |
Treatment Period 1: Probe Drugs
n=12 Participants
Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
|
Treatment Period 2: Short-term BI 425809 (After 3rd Dose) Plus Midazolam
n=12 Participants
Participants administered from Day 1 to Day 3 of Treatment Period 2 orally once daily 25 mg of BI 425809 with 240 ml of water. Within 1 hour after administration of BI 425809 on Day 3 of Treatment Period 2 participants administered orally a single dose of 2 mg of midazolam with 240 ml of water.
|
Treatment Period 2: BI 425809 Plus Probe Drugs
From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water.
|
|---|---|---|---|
|
Area Under the Concentration-time Curve of Digoxin From 0 to the Time of the Last Quantifiable Data Point (AUC0-tz)
|
9.71 ng*h/mL
Geometric Coefficient of Variation 38.4
|
9.51 ng*h/mL
Geometric Coefficient of Variation 37.0
|
—
|
PRIMARY outcome
Timeframe: Within 3 h before and up to 24h after administration of midazolam/probe drug cocktail. For detailed timeframe please see outcome measure description.Population: Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints.
Maximum measured concentration of midazolam in plasma (Cmax) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Short-term BI 425809 (after 3rd dose) plus midazolam": Within 3 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of midazolam on Day 3 of Treatment Period 2. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2.
Outcome measures
| Measure |
Treatment Period 1: Probe Drugs
n=13 Participants
Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
|
Treatment Period 2: Short-term BI 425809 (After 3rd Dose) Plus Midazolam
n=12 Participants
Participants administered from Day 1 to Day 3 of Treatment Period 2 orally once daily 25 mg of BI 425809 with 240 ml of water. Within 1 hour after administration of BI 425809 on Day 3 of Treatment Period 2 participants administered orally a single dose of 2 mg of midazolam with 240 ml of water.
|
Treatment Period 2: BI 425809 Plus Probe Drugs
n=12 Participants
From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water.
|
|---|---|---|---|
|
Maximum Concentration of Midazolam in Plasma (Cmax)
|
8.54 ng/mL
Geometric Coefficient of Variation 35.0
|
7.03 ng/mL
Geometric Coefficient of Variation 37.8
|
6.45 ng/mL
Geometric Coefficient of Variation 35.2
|
PRIMARY outcome
Timeframe: Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description.Population: Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints.
Maximum measured concentration of omeprazole in plasma (Cmax) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2.
Outcome measures
| Measure |
Treatment Period 1: Probe Drugs
n=13 Participants
Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
|
Treatment Period 2: Short-term BI 425809 (After 3rd Dose) Plus Midazolam
n=12 Participants
Participants administered from Day 1 to Day 3 of Treatment Period 2 orally once daily 25 mg of BI 425809 with 240 ml of water. Within 1 hour after administration of BI 425809 on Day 3 of Treatment Period 2 participants administered orally a single dose of 2 mg of midazolam with 240 ml of water.
|
Treatment Period 2: BI 425809 Plus Probe Drugs
From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water.
|
|---|---|---|---|
|
Maximum Concentration of Omeprazole in Plasma (Cmax)
|
220 ng/mL
Geometric Coefficient of Variation 89.0
|
208 ng/mL
Geometric Coefficient of Variation 72.8
|
—
|
PRIMARY outcome
Timeframe: Within 3 h before and up to 24h after administration of probe drug cocktail. For detailed timeframe please see outcome measure description.Population: Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints.
Maximum measured concentration of S-warfarin in plasma (Cmax) is presented. Arm "Treatment period 1: Probe drugs": Within 2 hours before and 0.5 hour (h), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 1 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 3 hours before and 0.5 h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24 h after administration of probe drug cocktail on Day 10 of Treatment Period 2.
Outcome measures
| Measure |
Treatment Period 1: Probe Drugs
n=13 Participants
Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
|
Treatment Period 2: Short-term BI 425809 (After 3rd Dose) Plus Midazolam
n=12 Participants
Participants administered from Day 1 to Day 3 of Treatment Period 2 orally once daily 25 mg of BI 425809 with 240 ml of water. Within 1 hour after administration of BI 425809 on Day 3 of Treatment Period 2 participants administered orally a single dose of 2 mg of midazolam with 240 ml of water.
|
Treatment Period 2: BI 425809 Plus Probe Drugs
From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water.
|
|---|---|---|---|
|
Maximum Concentration of S-warfarin in Plasma (Cmax)
|
535 ng/mL
Geometric Coefficient of Variation 22.8
|
552 ng/mL
Geometric Coefficient of Variation 26.9
|
—
|
PRIMARY outcome
Timeframe: Blood sampling was done before and up to 95 after administration of digoxin. For detailed timeframe please see outcome measure description.Population: Pharmacokinetic Analysis Set (PKS): All subjects in the Treated Set (TS) who provided at least 1 primary PK endpoint value not flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the evaluation of PK endpoints; the PKS was used for analyses of the primary and the further PK endpoints.
Maximum measured concentration of digoxin in plasma (Cmax) is presented. Time frame description: Arm "Treatment period 1: Probe drugs": Within 10 minutes before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 2 of Treatment Period 1. Arm "Treatment period 2: Steady state BI 425809 plus probe drugs": Within 4 hours before and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 47h, 71h, 95h after digoxin administration on Day 11 of Treatment Period 2.
Outcome measures
| Measure |
Treatment Period 1: Probe Drugs
n=12 Participants
Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
|
Treatment Period 2: Short-term BI 425809 (After 3rd Dose) Plus Midazolam
n=12 Participants
Participants administered from Day 1 to Day 3 of Treatment Period 2 orally once daily 25 mg of BI 425809 with 240 ml of water. Within 1 hour after administration of BI 425809 on Day 3 of Treatment Period 2 participants administered orally a single dose of 2 mg of midazolam with 240 ml of water.
|
Treatment Period 2: BI 425809 Plus Probe Drugs
From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water.
|
|---|---|---|---|
|
Maximum Concentration of Digoxin in Plasma (Cmax)
|
1.10 ng/mL
Geometric Coefficient of Variation 29.8
|
1.11 ng/mL
Geometric Coefficient of Variation 23.1
|
—
|
Adverse Events
Treatment Period 1: Probe Drugs
Treatment Period 2: BI 425809 Plus Probe Drugs
Overall Treatment
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Treatment Period 1: Probe Drugs
n=13 participants at risk
Treatment Period 1 (administration of reference treatment (R)-probe drugs only): On Day 1 of Treatment Period 1 participants administered orally a single dose of a probe drug cocktail consisting of 2 milligram (mg) midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water.
On Day 2 of treatment period 1 participants administered orally a single dose of 0.25 mg digoxin with 240 ml of water.
|
Treatment Period 2: BI 425809 Plus Probe Drugs
n=12 participants at risk
From Day 1 to Day 14 of Treatment Period 2 participants administered orally once daly 25 mg of BI 425809 with 240 ml of water. On Day 10 of Treatment Period 2 participants administered orally a single dose of a probe drug cocktail consisting of 2 mg midazolam, 10 mg warfarin, and 20 mg omeprazole with 240 milliliters of water. On Day 11 of Treatment Period 2 participants administered orally a single dose of 0.25 mg digoxin (probe drug) with 240 ml of water.
|
Overall Treatment
n=13 participants at risk
Single doses of probe drugs Midazolam-ratiopharm® 2 mg/mL solution, 1 mL (corresponds to 2 mg midazolam), Coumadin® 5 mg tablet, 2 tablets (corresponds to 10 mg warfarin) warfarin, Omeprazol STADA® 20 mg capsule (1 capsule (corresponds to 20 mg omeprazole)), Lanicor® 0.25 mg digoxin tablet (1 tablet (corresponds to 0.25 mg digoxin)) administered orally with 240 mL of water.
Multiple doses of 25 mg BI 425809 plus single doses of probe drugs midazolam (twice), warfarin, omeprazole, digoxin administered orally with 240 mL of water.
|
|---|---|---|---|
|
Infections and infestations
Nasopharyngitis
|
0.00%
0/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
16.7%
2/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
15.4%
2/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
Infections and infestations
Rhinitis
|
0.00%
0/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
8.3%
1/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
Infections and infestations
Conjunctivitis
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
0.00%
0/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
Infections and infestations
Oral herpes
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
0.00%
0/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
Infections and infestations
Upper respiratory tract infection
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
0.00%
0/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
Nervous system disorders
Headache
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
25.0%
3/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
30.8%
4/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
Eye disorders
Dry eye
|
0.00%
0/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
8.3%
1/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
0.00%
0/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
16.7%
2/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
15.4%
2/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
Renal and urinary disorders
Pollakiuria
|
0.00%
0/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
8.3%
1/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
General disorders
Fatigue
|
0.00%
0/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
33.3%
4/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
30.8%
4/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
|
Injury, poisoning and procedural complications
Arthropod bite
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
0.00%
0/12 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
7.7%
1/13 • From first drug administration until at least 11 days after last drug administration for each treatment arm, up to 36 days.
Residual effect period 11 days.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place