Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the effect of multiple oral doses of the strong CYP3A inducer carbamazepine on the pharmacokinetics of a single dose of BI 1810631 in plasma.
Interventions
DRUGZongertinib
Participants were administered a single dose of 60 milligrams (mg) of Zongertinib film-coated tablet orally on Day 1 with 240 milliliters (mL) of water after an overnight fast of at least 10 hours.
DRUGCarbamazepine
Participants received increasing doses of Carbamazepine once daily as extended-release tablets with 240 mL of water for 18 days, starting at 200 mg, then 400 mg, and finally 600 mg. Afterward, they continued taking 600 mg of Carbamazepine once daily for 6 days.
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SEQUENTIAL
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 in accordance with ICH-GCP and local legislation prior to admission to the trial
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG, the neurological examination, or the skin inspection) deviating from normal and assessed as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 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-∞) | One hour before administration of zongertinib, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 11, 12, 24, 36, 48, 72, 120, and 168 hours after administration. | Area under the concentration-time curve of Zongertinib in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). 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. |
| Maximum Measured Concentration of Zongertinib in Plasma (Cmax) | One hour before administration of zongertinib, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 11, 12, 24, 36, 48, 72, 120, and 168 hours after administration. | Maximum measured concentration of Zongertinib in plasma (Cmax). 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. |
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) | One hour before administration of zongertinib, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 11, 12, 24, 36, 48, 72, 120, and 168 hours after 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). 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 |
Countries
Germany
Participant flow
Recruitment details
The trial was an open-label, two-treatment, two-period, fixed-sequence crossover trial in healthy male Participants comparing the test treatment (T) with the reference treatment (R). Treatment R consisted of one single oral dose of 60 mg zongertinib as a film-coated tablet alone. Treatment T consisted of one single oral dose of 60 mg zongertinib as a film-coated tablet with multiple oral doses of carbamazepine, titrated from 200 mg once daily (q.d.) to 400 mg q.d., then to 600 mg q.d.
Pre-assignment details
A total of 16 participants entered the trial after being screened for eligibility, ensuring they met all inclusion and none of the exclusion criteria. They were allocated to the same treatment sequence to receive 2 treatments in a fixed order (R-T). All 16 received the first treatment (R), and 15 received the second (T). One participant did not start the second treatment due to a positive drug test result but completed the follow-up visit and was not considered to have prematurely discontinued.
Participants by arm
| Arm | Count |
|---|---|
| Zongertinib Alone (Reference)/ Zongertinib+Carbamazepine (Test) Zongertinib Alone:
In the reference treatment period, participants were administered a single dose of 60 milligrams (mg) of Zongertinib film-coated tablet orally on Day 1 with 240 milliliters (mL) of water after an overnight fast of at least 10 hours.
Zongertinib + Carbamazepine:
In the test treatment period (Period 2), participants were administered a single oral dose of 60 milligrams (mg) of Zongertinib in tablet form after an overnight fast of at least 10 hours, with 240 milliliters (mL) of water. This followed 18 days of pretreatment with increasing doses of Carbamazepine, starting at 200 mg, then 400 mg, and finally 600 mg, administered once daily as extended-release tablets with 240 mL of water. Additionally, subjects continued to receive 600 mg of Carbamazepine once daily for 6 days following Zongertinib administration. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Washout | Positive drug test. | 1 |
Baseline characteristics
| Characteristic | Zongertinib Alone (Reference)/ Zongertinib+Carbamazepine (Test) |
|---|---|
| Age, Continuous | 41.5 Years STANDARD_DEVIATION 11 |
| 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 |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 15 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 3 / 16 | 7 / 15 | 11 / 15 | 5 / 15 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 | 0 / 15 | 0 / 15 |
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-∞). 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.
Time frame: One hour before administration of zongertinib, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 11, 12, 24, 36, 48, 72, 120, and 168 hours after administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all participants in the treated set (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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Zongertinib Alone (Reference, R) | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 12334.87 hour * nanomole / liter (h*nmol/L) |
| Zongertinib+Carbamazepine (Test, T) | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 4500.05 hour * nanomole / liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model.90% CI: [31.96, 41.64]
Primary
Maximum Measured Concentration of Zongertinib in Plasma (Cmax)
Maximum measured concentration of Zongertinib in plasma (Cmax). 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.
Time frame: One hour before administration of zongertinib, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 11, 12, 24, 36, 48, 72, 120, and 168 hours after administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all participants in the treated set (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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Zongertinib Alone (Reference, R) | Maximum Measured Concentration of Zongertinib in Plasma (Cmax) | 914.01 nanomole / liter (nmol/L) |
| Zongertinib+Carbamazepine (Test, T) | Maximum Measured Concentration of Zongertinib in Plasma (Cmax) | 515.84 nanomole / liter (nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model.90% CI: [45.11, 70.6]
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). 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
Time frame: One hour before administration of zongertinib, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 11, 12, 24, 36, 48, 72, 120, and 168 hours after administration.
Population: Pharmacokinetic parameter analysis set (PKS): This set includes all participants in the treated set (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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Zongertinib Alone (Reference, R) | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 12138.26 hour * nanomole / liter (h*nmol/L) |
| Zongertinib+Carbamazepine (Test, T) | Area Under the Concentration-time Curve of Zongertinib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 4430.05 hour * nanomole / liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model.90% CI: [31.91, 41.74]