Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the effect of multiple doses of the strong CYP3A inhibitor and recommended P-glycoprotein (P-gp) inhibitor itraconazole on the pharmacokinetics of a single dose of zongertinib in plasma following oral administration.
Interventions
DRUGZongertinib
Zongertinib
DRUGItraconazole
Itraconazole
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 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 50 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 50 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 * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * History of relevant orthostatic hypotension, fainting spells, or blackouts Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours (h) prior to, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 47, 71, 119, 167 h for both periods, and additionally at 191, 215, 239, 263, and 287 h for period 2, after zongertinib administration. | Area under the concentration-time curve of zongertinib in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. |
| Maximum Measured Concentration of Zongertinib in Plasma (Cmax) | Within 3 hours (h) prior to, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 47, 71, 119, 167 h for both periods, and additionally at 191, 215, 239, 263, and 287 h for period 2, after zongertinib administration. | Maximum measured concentration of zongertinib in plasma (Cmax) is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours (h) prior to, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 47, 71, 119, 167 h for both periods, and additionally at 191, 215, 239, 263, and 287 h for period 2, after zongertinib administration. | Area under the concentration-time curve of zongertinib in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. |
Countries
Germany
Participant flow
Recruitment details
This was a non-randomised, open-label, two-treatment, two-period, fixed-sequence crossover trial in healthy men. There was one group of participants, each participant underwent the fixed sequence of Reference (R) followed by Test (T) treatment, with a washout period of ≥14 days between zongertinib (BI 1810631) administrations.
Pre-assignment details
All participants were screened for eligibility prior to participation in the trial. Participants attended a specialist site which ensured that they (the participants) strictly met all inclusion and none of the exclusion criteria. Participants were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Zongertinib Alone (R) / Zongertinib + Itraconazole (T) Treatment Period 1: a single oral dose of 15 milligrams (mg) zongertinib, film-coated tablet, was administered once on Day 1 (Day 1, Period 1, Visit 2), as reference treatment R.
Treatment Period 2: a single oral solution of 200 mg (10 mg/mL in a 20 milliliter (mL) solution) itraconazole was administered once daily over 14 days (\[total: 14 doses\], from Day -3 to Day 11, Period 2). On Day 1 (Day 1, Period 2, Visit 3), 4th day of itraconazole treatment, a single oral dose of 15 mg zongertinib was administered 1 hour (h) after itraconazole administration as test treatment T.
The two administrations of zongertinib were separated by a washout interval of at least 14 days.
Zongertinib and itraconazole were orally administered with 240 mL of water after an overnight fast of at least 10 h for zongertinib and 9 h for itraconazole. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Study Period 2 | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Zongertinib Alone (R) / Zongertinib + Itraconazole (T) |
|---|---|
| Age, Continuous | 33.3 Years STANDARD_DEVIATION 8.6 |
| 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 |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 4 / 16 | 6 / 16 | 10 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of zongertinib in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported.
Time frame: Within 3 hours (h) prior to, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 47, 71, 119, 167 h for both periods, and additionally at 191, 215, 239, 263, and 287 h for period 2, after zongertinib administration.
Population: Pharmacokinetic (PK) Set (PKS): this set included all participants in the treated set (TS) who provided at least one primary or secondary PK endpoint, and who was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Zongertinib Alone | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 3014 Nanomoles * hour per Liter |
| Zongertinib + Itraconazole | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 4255 Nanomoles * hour per Liter |
Comparison: The statistical model used was an analysis of variance (ANOVA) on the logarithmic scale. AUC0-∞ was log transformed (natural logarithm) prior to fitting the ANOVA model, considering the effect 'participant' as random and treatment as fixed.90% CI: [126.3, 157.7]ANOVA
Primary
Maximum Measured Concentration of Zongertinib in Plasma (Cmax)
Maximum measured concentration of zongertinib in plasma (Cmax) is reported.
Time frame: Within 3 hours (h) prior to, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 47, 71, 119, 167 h for both periods, and additionally at 191, 215, 239, 263, and 287 h for period 2, after zongertinib administration.
Population: PKS: this set included all participants in the TS who provided at least one primary or secondary PK endpoint, and who was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Zongertinib Alone | Maximum Measured Concentration of Zongertinib in Plasma (Cmax) | 138 Nanomoles per Liter |
| Zongertinib + Itraconazole | Maximum Measured Concentration of Zongertinib in Plasma (Cmax) | 175 Nanomoles per Liter |
Comparison: The statistical model used was an analysis of variance (ANOVA) on the logarithmic scale. Cmax was log transformed (natural logarithm) prior to fitting the ANOVA model, considering the effect 'participant' as random and treatment as fixed.90% CI: [106.6, 151]ANOVA
Secondary
Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of zongertinib in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.
Time frame: Within 3 hours (h) prior to, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 47, 71, 119, 167 h for both periods, and additionally at 191, 215, 239, 263, and 287 h for period 2, after zongertinib administration.
Population: PKS: this set included all participants in the TS who provided at least one primary or secondary PK endpoint, and who was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Zongertinib Alone | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 2892 Nanomoles * hour per Liter |
| Zongertinib + Itraconazole | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 4130 Nanomoles * hour per Liter |
Comparison: The statistical model used was an analysis of variance (ANOVA) on the logarithmic scale. AUC0-tz was log transformed (natural logarithm) prior to fitting the ANOVA model, considering the effect 'participant' as random and treatment as fixed.90% CI: [126, 161.9]ANOVA