Healthy
Conditions
Brief summary
The main objective of this trial is to assess the effect of multiple oral doses of zongertinib on the pharmacokinetics of midazolam, omeprazole and repaglinide.
Interventions
DRUGzongertinib
Participants received 120 mg Zongertinib daily as two 60 mg tablets.
DRUGmidazolam
Participants received 1 mg Midazolam as 0.5 mL oral solution.
DRUGomeprazole
Participants received 20 mg Omeprazole.
DRUGrepaglinide
Participants received a 0.5 mg Repaglinide.
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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
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 |
|---|---|---|
| Maximum Measured Concentration of Omeprazole in Plasma (Cmax) | Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule | The maximum measured concentration of omeprazole in plasma is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose. |
| Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule | The area under the concentration-time curve of omeprazole in plasma over the time interval from 0 extrapolated to infinity ((AUC0-∞) is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose. |
| Maximum Measured Concentration of Repaglinide in Plasma (Cmax) | Samples were collected on Day 1 (Period 1), Day 1 (Period 2), and Day 14 (Period 2). See endpoint description for the full sampling schedule | The maximum measured concentration of repaglinide in plasma is reported. Period 1 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 14): ≤15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 2.5, 3-, 4-,6-, and 24-hours post-dose. |
| Maximum Measured Concentration of Midazolam in Plasma (Cmax) | Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule | The maximum measured concentration of midazolam in plasma is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose. |
| Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | Samples were collected on Day 1 (Period 1), Day 1 (Period 2), and Day 14 (Period 2). See endpoint description for the full sampling schedule | The area under the concentration-time curve of repaglinide in plasma over the time interval from 0 extrapolated to infinity ((AUC0-∞) is reported. Period 1 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 14): ≤15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 2.5, 3-, 4-,6-, and 24-hours post-dose. |
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule | The area under the concentration-time curve of midazolam in plasma over the time interval from 0 extrapolated to infinity ((AUC0-∞) is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule | The area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose. |
| Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule | The area under the concentration-time curve of omeprazole in plasma over the time interval from 0 to the last quantifiable data point is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose. |
| Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Samples were collected on Day 1 (Period 1), Day 1 (Period 2), and Day 14 (Period 2). See endpoint description for the full sampling schedule | The area under the concentration-time curve of repaglinide in plasma over the time interval from 0 to the last quantifiable data poin is reported. Period 1 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 14): ≤15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 2.5, 3-, 4-,6-, and 24-hours post-dose. |
Countries
Germany
Participant flow
Recruitment details
This non-randomized, open-label, two-period, fixed-sequence trial evaluated the effect of multiple oral doses of zongertinib on the single-dose pharmacokinetics of midazolam, omeprazole, and repaglinide in healthy male subjects to assess potential drug-drug interactions.
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 to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Repaglinide+Midazolam+Omeprazole (Reference)/ Zongertinib+Repaglinide+Midazolam+Omeprazole (Test) Reference (Repaglinide + Midazolam + Omeprazole)
In the reference treatment period (Period 1), participants received 0.5 mg repaglinide tablet (Day 1, after ≥10 h fast; Reference Treatment 1). On Day 2, they received 1 mg midazolam (0.5 mL oral solution) with 20 mg omeprazole tablet under the same fasting conditions (Reference Treatment 2).
Test (Zongertinib + Repaglinide + Midazolam + Omeprazole)
In the test treatment period (Period 2), participants received multiple once-daily doses of 120 mg zongertinib from Day 1 to Day 15. A single 0.5 mg repaglinide tablet was co-administered on Day 1 (Test Treatment 1) and Day 14 (Test Treatment 3), and a single dose of the probe drug cocktail containing 1 mg midazolam (0.5 mL oral solution) and 20 mg omeprazole tablet was co-administered on Day 2 (Test Treatment 2) and Day 15 (Test Treatment 4). | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 2: (Test Period) (15 days) | Adverse Event | 1 |
| Period 2: (Test Period) (15 days) | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Repaglinide+Midazolam+Omeprazole (Reference)/ Zongertinib+Repaglinide+Midazolam+Omeprazole (Test) |
|---|---|
| Age, Continuous | 35.6 Years STANDARD_DEVIATION 12.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 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 | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 2 / 16 | 2 / 16 | 4 / 16 | 4 / 14 | 9 / 14 | 2 / 14 | 4 / 14 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞)
The area under the concentration-time curve of midazolam in plasma over the time interval from 0 extrapolated to infinity ((AUC0-∞) is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose.
Time frame: Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Two subjects were discontinued by the investigator before Zongertinib administration on Day 2, leading to fewer subjects in Test Treatment Arm 2 and 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide Alone (Reference Treatment 1) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | 41400 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 33.5 |
| Repaglinide with a single dose of zongertinib (Test Treatment 1) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | 44200 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 37.3 |
| Repaglinide after multiple doses of zongertinib (Test Treatment 3) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | 43400 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 27.9 |
Comparison: The relative bioavailability of midazolam was assessed by comparing Midazolam + Omeprazole with a single dose of zongertinib (Test Treatment 2) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [98.57, 117.9]
Comparison: The relative bioavailability of midazolam was assessed by comparing Midazolam + Omeprazole after multiple doses of zongertinib (Test Treatment 4) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [95.41, 116.93]
Primary
Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞)
The area under the concentration-time curve of omeprazole in plasma over the time interval from 0 extrapolated to infinity ((AUC0-∞) is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose.
Time frame: Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Only participants with evaluable results were reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide Alone (Reference Treatment 1) | Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | 378 hour * nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 69.7 |
| Repaglinide with a single dose of zongertinib (Test Treatment 1) | Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | 359 hour * nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 66.9 |
| Repaglinide after multiple doses of zongertinib (Test Treatment 3) | Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | 296 hour * nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 60.2 |
Comparison: The relative bioavailability of omeprazole was assessed by comparing Midazolam + Omeprazole with a single dose of zongertinib (Test Treatment 2) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [75.96, 122.72]
Comparison: The relative bioavailability of omeprazole was assessed by comparing Midazolam + Omeprazole after multiple doses of zongertinib (Test Treatment 4) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [61.86, 130.2]
Primary
Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞)
The area under the concentration-time curve of repaglinide in plasma over the time interval from 0 extrapolated to infinity ((AUC0-∞) is reported. Period 1 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 14): ≤15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 2.5, 3-, 4-,6-, and 24-hours post-dose.
Time frame: Samples were collected on Day 1 (Period 1), Day 1 (Period 2), and Day 14 (Period 2). See endpoint description for the full sampling schedule
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Two subjects were discontinued by the investigator before Zongertinib administration on Day 2, leading to fewer subjects in Test Treatment 3 Arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide Alone (Reference Treatment 1) | Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | 28100 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 58 |
| Repaglinide with a single dose of zongertinib (Test Treatment 1) | Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | 31200 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 49.2 |
| Repaglinide after multiple doses of zongertinib (Test Treatment 3) | Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC₀-∞) | 37300 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 48.7 |
Comparison: The relative bioavailability of Repaglinide was assessed by comparing Repaglinide administered with a single dose of zongertinib (Test Treatment 1) to Repaglinide administered alone (Reference Treatment 1). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [96.9, 127.1]
Comparison: The relative bioavailability of Repaglinide was assessed by comparing Repaglinide administered after multiple doses of zongertinib (Test Treatment 3) to Repaglinide administered alone (Reference Treatment 1). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [110.35, 153.39]
Primary
Maximum Measured Concentration of Midazolam in Plasma (Cmax)
The maximum measured concentration of midazolam in plasma is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose.
Time frame: Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Two subjects were discontinued by the investigator before Zongertinib administration on Day 2, leading to fewer subjects in Test Treatment Arm 2 and 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide Alone (Reference Treatment 1) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) | 17700 Picomoles per liter (pmol/L) | Geometric Coefficient of Variation 25.8 |
| Repaglinide with a single dose of zongertinib (Test Treatment 1) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) | 19700 Picomoles per liter (pmol/L) | Geometric Coefficient of Variation 33 |
| Repaglinide after multiple doses of zongertinib (Test Treatment 3) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) | 20800 Picomoles per liter (pmol/L) | Geometric Coefficient of Variation 26 |
Comparison: The relative bioavailability of midazolam was assessed by comparing Midazolam + Omeprazole with a single dose of zongertinib (Test Treatment 2) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [100.92, 121.52]
Comparison: The relative bioavailability of midazolam was assessed by comparing Midazolam + Omeprazole after multiple doses of zongertinib (Test Treatment 4) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [108.3, 126.81]
Primary
Maximum Measured Concentration of Omeprazole in Plasma (Cmax)
The maximum measured concentration of omeprazole in plasma is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose.
Time frame: Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Only participants with evaluable results were reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide Alone (Reference Treatment 1) | Maximum Measured Concentration of Omeprazole in Plasma (Cmax) | 165 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 91.7 |
| Repaglinide with a single dose of zongertinib (Test Treatment 1) | Maximum Measured Concentration of Omeprazole in Plasma (Cmax) | 131 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 78.3 |
| Repaglinide after multiple doses of zongertinib (Test Treatment 3) | Maximum Measured Concentration of Omeprazole in Plasma (Cmax) | 101 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 79.3 |
Comparison: The relative bioavailability of omeprazole was assessed by comparing Midazolam + Omeprazole with a single dose of zongertinib (Test Treatment 2) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [49.9, 126.3]
Comparison: The relative bioavailability of omeprazole was assessed by comparing Midazolam + Omeprazole after multiple doses of zongertinib (Test Treatment 4) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [44.69, 86.2]
Primary
Maximum Measured Concentration of Repaglinide in Plasma (Cmax)
The maximum measured concentration of repaglinide in plasma is reported. Period 1 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 14): ≤15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 2.5, 3-, 4-,6-, and 24-hours post-dose.
Time frame: Samples were collected on Day 1 (Period 1), Day 1 (Period 2), and Day 14 (Period 2). See endpoint description for the full sampling schedule
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Two subjects were discontinued by the investigator before Zongertinib administration on Day 2, leading to fewer subjects in Test Treatment 3 Arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide Alone (Reference Treatment 1) | Maximum Measured Concentration of Repaglinide in Plasma (Cmax) | 20200 Picomoles per liter (pmol/L) | Geometric Coefficient of Variation 52.6 |
| Repaglinide with a single dose of zongertinib (Test Treatment 1) | Maximum Measured Concentration of Repaglinide in Plasma (Cmax) | 23600 Picomoles per liter (pmol/L) | Geometric Coefficient of Variation 40.9 |
| Repaglinide after multiple doses of zongertinib (Test Treatment 3) | Maximum Measured Concentration of Repaglinide in Plasma (Cmax) | 29700 Picomoles per liter (pmol/L) | Geometric Coefficient of Variation 36.8 |
Comparison: The relative bioavailability of Repaglinide was assessed by comparing Repaglinide administered with a single dose of zongertinib (Test Treatment 1) to Repaglinide administered alone (Reference Treatment 1). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [105.56, 129.84]
Comparison: The relative bioavailability of Repaglinide was assessed by comparing Repaglinide administered after multiple doses of zongertinib (Test Treatment 3) to Repaglinide administered alone (Reference Treatment 1). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [123.53, 168.71]
Secondary
Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
The area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose.
Time frame: Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Two subjects were discontinued by the investigator before Zongertinib administration on Day 2, leading to fewer subjects in Test Treatment Arm 2 and 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide Alone (Reference Treatment 1) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 39600 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 33.6 |
| Repaglinide with a single dose of zongertinib (Test Treatment 1) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 42700 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 38.1 |
| Repaglinide after multiple doses of zongertinib (Test Treatment 3) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 41700 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 27.7 |
Comparison: The relative bioavailability of midazolam was assessed by comparing Midazolam + Omeprazole with a single dose of zongertinib (Test Treatment 2) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [98.79, 119.41]
Comparison: The relative bioavailability of midazolam was assessed by comparing Midazolam + Omeprazole after multiple doses of zongertinib (Test Treatment 4) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [95.49, 117.73]
Secondary
Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
The area under the concentration-time curve of omeprazole in plasma over the time interval from 0 to the last quantifiable data point is reported. Period 1 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 hours post-dose. Period 2 (Day 2): 15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 12 h post-dose. Period 2 (Day 15): 15 min pre-dose, and at 15, 30, 45 min; 1, 1.5, 2, 4, 6, 8, 10, 11, 12 hours post-dose.
Time frame: Samples were collected on Day 2 (Period 1), Day 2 (Period 2), and Day 15 (Period 2). See endpoint description for the full sampling schedule
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Only participants with evaluable results were reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide Alone (Reference Treatment 1) | Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 287 h*ng/mL | Geometric Coefficient of Variation 78.3 |
| Repaglinide with a single dose of zongertinib (Test Treatment 1) | Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 304 h*ng/mL | Geometric Coefficient of Variation 72.8 |
| Repaglinide after multiple doses of zongertinib (Test Treatment 3) | Area Under the Concentration-time Curve of Omeprazole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 267 h*ng/mL | Geometric Coefficient of Variation 61.8 |
Comparison: The relative bioavailability of omeprazole was assessed by comparing Midazolam + Omeprazole with a single dose of zongertinib (Test Treatment 2) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [79.9, 146.35]
Comparison: The relative bioavailability of omeprazole was assessed by comparing Midazolam + Omeprazole after multiple doses of zongertinib (Test Treatment 4) to Midazolam + Omeprazole (Reference Treatment 2). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [75.01, 127.53]
Secondary
Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
The area under the concentration-time curve of repaglinide in plasma over the time interval from 0 to the last quantifiable data poin is reported. Period 1 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 1): Up to 3 hours pre-dose and at 15, 30, and 45 minutes, and 1, 1.5, 2, 2.5, 3-, 4-, 6-, and 24-hours post-dose. Period 2 (Day 14): ≤15 min pre-dose and at 15, 30, 45 min; 1, 1.5, 2, 2.5, 3-, 4-,6-, and 24-hours post-dose.
Time frame: Samples were collected on Day 1 (Period 1), Day 1 (Period 2), and Day 14 (Period 2). See endpoint description for the full sampling schedule
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide 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. Two subjects were discontinued by the investigator before Zongertinib administration on Day 2, leading to fewer subjects in Test Treatment 3 Arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Repaglinide Alone (Reference Treatment 1) | Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 27700 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 58.3 |
| Repaglinide with a single dose of zongertinib (Test Treatment 1) | Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 30700 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 50.5 |
| Repaglinide after multiple doses of zongertinib (Test Treatment 3) | Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 36700 Hours × picomoles per liter (h*pmol/L) | Geometric Coefficient of Variation 48.7 |
Comparison: The relative bioavailability of Repaglinide was assessed by comparing Repaglinide administered with a single dose of zongertinib (Test Treatment 1) to Repaglinide administered alone (Reference Treatment 1). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [96.58, 127.24]
Comparison: The relative bioavailability of Repaglinide was assessed by comparing Repaglinide administered after multiple doses of zongertinib (Test Treatment 3) to Repaglinide administered alone (Reference Treatment 1). The ratio of geometric means (Test/Reference) with 90% two-sided confidence intervals (CIs) was calculated. The log-transformed difference (log\[T\]-log\[R\]) was estimated using least squares means from ANOVA and then back-transformed to the original scale.90% CI: [109.7, 153.59]