Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the relative bioavailability of a single dose of bupropion when given alone (Reference) compared with co-administration (Test) with BI 1358894 in healthy volunteers.
Interventions
DRUGElontril
Tablet
DRUGBI 1358894
Film coated tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female 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 prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation * Male subjects, or female subjects who meet any of the following criteria from at least 30 days before the first administration of trial medication until 30 days after trial completion: * Sexually abstinent * Use of adequate contraception, e.g. any of the following methods plus condom: implants, injectables, intrauterine device * A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) * Surgically sterilised (including hysterectomy) * Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with levels of follicle stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory)
Exclusion criteria
* Any finding in the medical examination (including safety laboratory, 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 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 * 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 Bupropion in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Up to 120 hours (h) after administration of bupropion (for detailed timeframe please see description). | Area under the concentration-time curve of bupropion in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Time Frame: Within 3 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm bupropion alone (Reference (R)). Within 0.5 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm BI 1358894 + bupropion (Test (T)). |
| Maximum Measured Concentration of Bupropion in Plasma (Cmax) | Up to 120 hours (h) after administration of bupropion (for detailed timeframe please see description). | Maximum measured concentration of bupropion in plasma (Cmax) is presented. Timeframe: Within 3 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm bupropion alone (Reference (R)). Within 0.5 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm BI 1358894 + bupropion (Test (T)). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Bupropion in Plasma Over the Time Interval From 0 to Infinity (AUC0-∞) | Up to 120 hours (h) after administration of bupropion (for detailed timeframe please see description). | Area under the concentration-time curve of bupropion in plasma over the time interval from 0 to infinity (AUC0-∞) is presented. Time Frame: Within 3 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm bupropion alone (Reference (R)). Within 0.5 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm BI 1358894 + bupropion (Test (T)). |
Countries
Germany
Participant flow
Recruitment details
This was a phase I, open-label, two-period fixed sequence trial to evaluate the effect of multiple doses of BI 1358894 on the pharmacokinetics of bupropion in healthy volunteers.
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 |
|---|---|
| Bupropion Alone (Reference (R)) Then BI 1358894 + Bupropion (Test (T)) Reference (R): Participants were administered on Day 1 of Visit 2 (Period: Reference) orally a single dose of 150 milligram (mg) of bupropion sustained release (SR) tablet (Elontril®) under fed conditions with 240 milliliter (mL) of water.
Test (T): From Day -14 to Day 5 of Visit 3 (Period: Test) participants were administered orally once daily 2 film coated tablets of 50 mg of BI 1358894 (total dosage 100 mg/day) under fed conditions with 240 mL of water. On the 15th day of BI 1358894 administration (i.e. Day 1 of Visit 3 (Period: Test)) a single dose of 150 mg of bupropion was co-administered.
The single-dose administrations of bupropion in Periods Reference and Test were to be separated by an interval of 21 days. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Test | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Bupropion Alone (Reference (R)) Then BI 1358894 + Bupropion (Test (T)) |
|---|---|
| Age, Continuous | 38.7 Years STANDARD_DEVIATION 11.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 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 | 18 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 | 0 / 17 |
| other Total, other adverse events | 4 / 18 | 9 / 18 | 3 / 17 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 17 |
Outcome results
Primary
Area Under the Concentration-time Curve of Bupropion in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of bupropion in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. Time Frame: Within 3 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm bupropion alone (Reference (R)). Within 0.5 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm BI 1358894 + bupropion (Test (T)).
Time frame: Up to 120 hours (h) after administration of bupropion (for detailed timeframe please see description).
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least 1 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_LEAST_SQUARES_MEAN) |
|---|---|---|
| Bupropion Alone (Reference (R)) | Area Under the Concentration-time Curve of Bupropion in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 2953 hours * nanomole/Liter |
| BI 1358894 + Bupropion (Test (T)) | Area Under the Concentration-time Curve of Bupropion in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 2795 hours * nanomole/Liter |
Comparison: The statistical model used for the analysis of the primary endpoints was an Analysis of Variance (ANOVA) model. The model included effects accounting for the following sources of variation: 'subjects' and 'treatment'. The effect 'subjects' was considered as random, whereas the effect 'treatment' was considered as fixed.90% CI: [86.3, 103.8]
Primary
Maximum Measured Concentration of Bupropion in Plasma (Cmax)
Maximum measured concentration of bupropion in plasma (Cmax) is presented. Timeframe: Within 3 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm bupropion alone (Reference (R)). Within 0.5 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm BI 1358894 + bupropion (Test (T)).
Time frame: Up to 120 hours (h) after administration of bupropion (for detailed timeframe please see description).
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least 1 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_LEAST_SQUARES_MEAN) |
|---|---|---|
| Bupropion Alone (Reference (R)) | Maximum Measured Concentration of Bupropion in Plasma (Cmax) | 262 nanomole/Liter |
| BI 1358894 + Bupropion (Test (T)) | Maximum Measured Concentration of Bupropion in Plasma (Cmax) | 237 nanomole/Liter |
Comparison: The statistical model used for the analysis of the primary endpoints was an Analysis of Variance (ANOVA) model. The model included effects accounting for the following sources of variation: 'subjects' and 'treatment'. The effect 'subjects' was considered as random, whereas the effect 'treatment' was considered as fixed.90% CI: [74.3, 110.7]
Secondary
Area Under the Concentration-time Curve of Bupropion in Plasma Over the Time Interval From 0 to Infinity (AUC0-∞)
Area under the concentration-time curve of bupropion in plasma over the time interval from 0 to infinity (AUC0-∞) is presented. Time Frame: Within 3 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm bupropion alone (Reference (R)). Within 0.5 hours (h) before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h after bupropion administration for the arm BI 1358894 + bupropion (Test (T)).
Time frame: Up to 120 hours (h) after administration of bupropion (for detailed timeframe please see description).
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least 1 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_LEAST_SQUARES_MEAN) |
|---|---|---|
| Bupropion Alone (Reference (R)) | Area Under the Concentration-time Curve of Bupropion in Plasma Over the Time Interval From 0 to Infinity (AUC0-∞) | 3003 hours * nanomole/Liter |
| BI 1358894 + Bupropion (Test (T)) | Area Under the Concentration-time Curve of Bupropion in Plasma Over the Time Interval From 0 to Infinity (AUC0-∞) | 2855 hours * nanomole/Liter |
Comparison: The statistical model used for the analysis of the primary endpoints was an Analysis of Variance (ANOVA). The model included effects accounting for the following sources of variation: 'subjects' and 'treatment'. The effect 'subjects' was considered as random, whereas the effect 'treatment' was considered as fixed.90% CI: [86.7, 104.3]