Healthy
Conditions
Brief summary
For Part 1 of the trial, the main objective is to assess the effect of a single dose of zongertinib on the pharmacokinetics of a single dose of dabigatran-etexilate. For Part 2 of the trial, the main objective is to assess the effect of zongertinib at steady-state on the pharmacokinetics of a single dose of rosuvastatin, metformin and furosemide (administered as a cocktail).
Interventions
DRUGZongertinib
A 120 mg dose on Day 1 of period 2 (Part 1) OR daily (Part 2) with 240 mL of water after an overnight fast of at least 10 hours.
A 150 mg dose on Day 1 of each period with 240 mL of water after an overnight fast of at least 10 hours.
DRUGRosuvastatin
A 10 mg dose on Day 1 of each period with 240 mL of water after an overnight fast of at least 10 hours.
DRUGMetformin hydrochloride
A 10 mg dose on Day 1 of each period with 240 mL of water after an overnight fast of at least 10 hours.
DRUGFurosemide
A 1 mg dose on Day 1 of each period with 240 mL of water after an overnight fast of at least 10 hours.
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
fixed-sequence crossover
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
: * Healthy male subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests * Age of 18 to 55 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) * Signed and dated written informed consent in accordance with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial
Exclusion criteria
: * Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 millimetre(s) of mercury (mmHg), diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 beats per minute (bpm) * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease assessed as clinically relevant by the investigator Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Maximum Measured Concentration of Furosemide in Plasma (Cmax) | Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T). | Maximum measured concentration of furosemide in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 2: Maximum Measured Concentration of Rosuvastatin in Plasma (Cmax) | Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T). | Maximum measured concentration of rosuvastatin in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 2: Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T). | Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 2: Maximum Measured Concentration of Metforminin in Plasma (Cmax) | Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T). | Maximum measured concentration of metforminin in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 2: Area Under the Concentration-time Curve of Furosemide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T). | Area under the concentration-time curve of furosemide in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 1: Area Under the Concentration-time Curve of Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours (h) before dabigatran-etexilate administration (R only), within 3 h prior to zongertinib administration (T only), and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48 h after dabigatran-etexilate administration (R and T). | Area under the concentration-time curve of dabigatran in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 1: Maximum Measured Concentration of Dabigatran in Plasma (Cmax) | Within 3 hours (h) before dabigatran-etexilate administration (R only), within 3 h prior to zongertinib administration (T only), and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48 h after dabigatran-etexilate administration (R and T). | Maximum measured concentration of dabigatran in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 2: Area Under the Concentration-time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T). | Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Area Under the Concentration-time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T). | Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 2: Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T). | Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 2: Area Under the Concentration-time Curve of Furosemide in in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T). | Area under the concentration-time curve of furosemide in in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
| Part 1: Area Under the Concentration-time Curve of Dabigatran in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours (h) before dabigatran-etexilate administration (R only), within 3 h prior to zongertinib administration (T only), and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48 h after dabigatran-etexilate administration (R and T). | Area under the concentration-time curve of dabigatran in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale. |
Countries
Germany
Participant flow
Recruitment details
This was a non-randomised, open-label, 2-period fixed-sequence crossover trial in healthy male participants to compare the test treatments (T: zongertinib and dabigatran-etexilate in part 1; zongertinib, rosuvastatin, metformin, furosemide in part 2) to the reference treatments (R: dabigatran-etexilate in part 1; rosuvastatin, metformin, furosemide in part 2).
Pre-assignment details
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 included in the trial if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Dabigatran-etexilate (R), Then Zongertinib and Dabigatran-etexilate (T) Participants were administered a 150 milligram (mg) dabigatran-etexilate hard capsule orally with 240 milliliters (mL) of water after an overnight fast of at least 10 hours on Day 1 of period 1 (Reference treatment, R). After a wash-out period, participants were administered two 60 mg film-coated tablets of zongertinib (total dose: 120 mg) orally, and a 150 mg dabigatran-etexilate hard capsule orally on Day 1 of period 2 (Test treatment, T). Both medications were administered with 240 mL of water after an overnight fast of at least 10 hours. | 16 |
| Part 2: Drug Cocktail (R), Then Zongertinib and Drug Cocktail (T) Participants were administered a cocktail consisting of a 10 mg rosuvastatin film-coated tablet, a 10 mg metformin oral solution, and a 1 mg furosemide oral solution with 240 mL of water after an overnight fast of at least 10 hours on Day 1 of period 1 (Reference treatment, R). In period 2, from Day -9 to Day 3, participants were administered two 60 mg film-coated tablets of zongertinib (total dose: 120 mg) orally every day. On Day 1, participants were also administered a cocktail consisting of a 10 mg rosuvastatin film-coated tablet, a 10 mg metformin oral solution, and a 1 mg furosemide oral solution (Test treatment, T). Every medication was administered with 240 mL of water after an overnight fast of at least 10 hours. | 16 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Transition period | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Part 2: Drug Cocktail (R), Then Zongertinib and Drug Cocktail (T) | Total | Part 1: Dabigatran-etexilate (R), Then Zongertinib and Dabigatran-etexilate (T) |
|---|---|---|---|
| Age, Continuous | 37.8 Years STANDARD_DEVIATION 11.2 | 36.9 Years STANDARD_DEVIATION 10.2 | 35.9 Years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 32 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 30 Participants | 15 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 16 Participants | 32 Participants | 16 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 15 | 0 / 15 | 0 / 16 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 2 / 16 | 0 / 15 | 3 / 15 | 5 / 16 | 9 / 16 | 5 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 | 0 / 15 | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Part 1: Area Under the Concentration-time Curve of Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of dabigatran in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 hours (h) before dabigatran-etexilate administration (R only), within 3 h prior to zongertinib administration (T only), and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48 h after dabigatran-etexilate administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 1: all part 1 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 1: Area Under the Concentration-time Curve of Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 725.25 hour*nanogram/milliliter (h*ng/mL) |
| Zongertinib and dabigatran-etexilate (T) | Part 1: Area Under the Concentration-time Curve of Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 971.67 hour*nanogram/milliliter (h*ng/mL) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [105.52, 170.11]
Primary
Part 1: Maximum Measured Concentration of Dabigatran in Plasma (Cmax)
Maximum measured concentration of dabigatran in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 hours (h) before dabigatran-etexilate administration (R only), within 3 h prior to zongertinib administration (T only), and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48 h after dabigatran-etexilate administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 1: all part 1 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 1: Maximum Measured Concentration of Dabigatran in Plasma (Cmax) | 89.01 nanogram/milliliter (ng/mL) |
| Zongertinib and dabigatran-etexilate (T) | Part 1: Maximum Measured Concentration of Dabigatran in Plasma (Cmax) | 110.53 nanogram/milliliter (ng/mL) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [96.13, 160.43]
Primary
Part 2: Area Under the Concentration-time Curve of Furosemide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of furosemide in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 2: all part 2 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 2: Area Under the Concentration-time Curve of Furosemide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 172.84 hour*nanomole/liter (h*nmol/L) |
| Zongertinib and dabigatran-etexilate (T) | Part 2: Area Under the Concentration-time Curve of Furosemide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 238.43 hour*nanomole/liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [120.17, 158.36]
Primary
Part 2: Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 2: all part 2 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 2: Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 1355.69 hour*nanomole/liter (h*nmol/L) |
| Zongertinib and dabigatran-etexilate (T) | Part 2: Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 1125.52 hour*nanomole/liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [76.48, 90.12]
Primary
Part 2: Area Under the Concentration-time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 2: all part 2 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 2: Area Under the Concentration-time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 102.98 hour*nanomole/liter (h*nmol/L) |
| Zongertinib and dabigatran-etexilate (T) | Part 2: Area Under the Concentration-time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 237.15 hour*nanomole/liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [195.68, 271.04]
Primary
Part 2: Maximum Measured Concentration of Furosemide in Plasma (Cmax)
Maximum measured concentration of furosemide in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 2: all part 2 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 2: Maximum Measured Concentration of Furosemide in Plasma (Cmax) | 75.73 nanomole/liter (nmol/L) |
| Zongertinib and dabigatran-etexilate (T) | Part 2: Maximum Measured Concentration of Furosemide in Plasma (Cmax) | 113.45 nanomole/liter (nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [116.12, 193.25]
Primary
Part 2: Maximum Measured Concentration of Metforminin in Plasma (Cmax)
Maximum measured concentration of metforminin in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 2: all part 2 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 2: Maximum Measured Concentration of Metforminin in Plasma (Cmax) | 230.25 nanomole/liter (nmol/L) |
| Zongertinib and dabigatran-etexilate (T) | Part 2: Maximum Measured Concentration of Metforminin in Plasma (Cmax) | 174.00 nanomole/liter (nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [68.03, 83.95]
Primary
Part 2: Maximum Measured Concentration of Rosuvastatin in Plasma (Cmax)
Maximum measured concentration of rosuvastatin in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 2: all part 2 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 2: Maximum Measured Concentration of Rosuvastatin in Plasma (Cmax) | 8.87 nanomole/liter (nmol/L) |
| Zongertinib and dabigatran-etexilate (T) | Part 2: Maximum Measured Concentration of Rosuvastatin in Plasma (Cmax) | 26.75 nanomole/liter (nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [247.19, 368.19]
Secondary
Part 1: Area Under the Concentration-time Curve of Dabigatran in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of dabigatran in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 hours (h) before dabigatran-etexilate administration (R only), within 3 h prior to zongertinib administration (T only), and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48 h after dabigatran-etexilate administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 1: all part 1 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 1: Area Under the Concentration-time Curve of Dabigatran in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 700.45 hour*nanogram/milliliter (h*ng/mL) |
| Zongertinib and dabigatran-etexilate (T) | Part 1: Area Under the Concentration-time Curve of Dabigatran in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 942.02 hour*nanogram/milliliter (h*ng/mL) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [105.56, 171.34]
Secondary
Part 2: Area Under the Concentration-time Curve of Furosemide in in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of furosemide in in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 2: all part 2 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 2: Area Under the Concentration-time Curve of Furosemide in in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 164.01 hour*nanomole/liter (h*nmol/L) |
| Zongertinib and dabigatran-etexilate (T) | Part 2: Area Under the Concentration-time Curve of Furosemide in in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 235.33 hour*nanomole/liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [123.78, 166.33]
Secondary
Part 2: Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 2: all part 2 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 2: Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 1343.93 hour*nanomole/liter (h*nmol/L) |
| Zongertinib and dabigatran-etexilate (T) | Part 2: Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 1113.21 hour*nanomole/liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [76.27, 89.96]
Secondary
Part 2: Area Under the Concentration-time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of rosuvastatin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.
Time frame: Within 3 h prior to drug cocktail administration (R), within 15 minutes prior to drug cocktail and zongertinib administration (T), and 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after drug cocktail administration (R and T).
Population: Pharmacokinetic parameter analysis set (PKS) restricted to part 2: all part 2 participants in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Dabigatran-etexilate (R) | Part 2: Area Under the Concentration-time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 93.10 hour*nanomole/liter (h*nmol/L) |
| Zongertinib and dabigatran-etexilate (T) | Part 2: Area Under the Concentration-time Curve of Rosuvastatin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 231.53 hour*nanomole/liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an ANOVA model on the logarithmic scale. The PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model, which included effects accounting for the following sources of variation: participant (considered as random) and treatment (considered as fixed). These quantities were then back-transformed to the original scale.90% CI: [211.03, 293.07]