Healthy
Conditions
Brief summary
The main objective of Part 1 of this trial is to investigate the absolute bioavailability of BI 1358894 with an intravenous microdose formulation containing labelled \[C-14\] BI 1358894 and an unlabelled oral tablet formulation of BI 1358894 in healthy male subjects. The main objective of Part 2 of this trial is to investigate the relative bioavailability of BI 1358894 administered as an oral suspension.
Interventions
DRUGBI 1358894
Tablet
DRUGBI 1358894 (C-14) intravenous solution
BI 1358894 mixed with \[carbon labelled (C-14)\] BI 1358894
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part 1: non-randomized, fixed-sequence design Part 2: randomized, two-period, two-sequence, crossover design
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 (BP, PR), 12-lead ECG, and clinical laboratory tests * Age of 18 to 55 years (inclusive) * 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 GCP and local legislation * Male subjects who meet any of the following criteria from at least 30 days before the first administration of trial medication until 90 days after trial completion: * Use of adequate contraception of the female partner, e.g. any of the following methods plus condom: implants, injectables, combined oral or vaginal contraceptives, intrauterine device that started at least 2 months prior to first study drug administration or barrier method (e.g. diaphragm with spermicide) or, * Sexually abstinent or * A vasectomy performed at least 1 year prior to screening (with medical assessment of the surgical success) or * Surgically sterilised female partner (including hysterectomy, bilateral tubal occlusion or bilateral oophorectomy) or * Postmenopausal female partner, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with FSH (follicle stimulating hormone) above 40 U/L and estradiol below 30 ng/L is confirmatory)
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 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 40 to 100 bpm * C-reactive protein (CRP) \> upper limit of normal (ULN), liver or kidney parameter above ULN * 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 * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Area Under the Concentration-time Curve of BI 1358894 Over the Time Interval From 0 to Infinity After i.v. Administration and After Oral Administration (AUC0-infinity) | Within 2 hours (h) before and at 15 minutes (min), 30 min, 1 h, 1.5, 2, 3, 4, 5, 5.083, 5.16, 5.25, 5.5, 5.75, 6, 6.5, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after oral dose of BI 1358894 on Day 1 of Period 1. Continues in description. | Area under the concentration-time curve of BI 1358894 over the time interval from 0 to infinity after i.v. administration and after oral administration (AUC0-infinity) is reported. The values were calculated using the Analysis of variance (ANOVA) model which included effects accounting for the following sources of variation: 'subjects' and 'formulation'. The effect 'subjects' was considered as random, whereas 'formulation' was considered as fixed. Standard error is actually geometric standard error. Time Frame: For BI 1358894 (C-14) 100 ug i.v samples were collected at 5h, 5.083, 5.16, 5.25, 5.5, 5.75, 6, 6.5, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after oral dose of BI 1358894 on Day 1 of Period 1. |
| Part 2: Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to 312 h (AUC 0-312) | Within 2 hours (h) before drug administration and at 15 minutes (min), 30 min, 1 h, 1.5, 2, 3, 4, 5, 6, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after administration of BI 1358894. | Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 to 312 h (AUC 0-312) is reported. The values were calculated using the Analysis of variance (ANOVA) model which included effects accounting for the following sources of variation: 'sequence or block', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Standard error is actually geometric standard error. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Maximum Measured Concentration of BI 1358894 in Plasma After i.v. Administration and After Oral Administration (Cmax) | Within 2 hours before and at 15 minutes (min), 30 min, 1 hour (h), 1.5, 2, 3, 4, 5, 5.083, 5.16, 5.25, 5.5, 5.75, 6, 6.5, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after oral dose of BI 1358894 on Day 1 of Period 1. Continues in description. | Maximum measured concentration of BI 1358894 in plasma after i.v. administration and after oral administration(Cmax) is reported. Time Frame: For BI 1358894 (C-14) 100 ug i.v samples were collected at 5h, 5.083, 5.16, 5.25, 5.5, 5.75, 6, 6.5, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after oral dose of BI 1358894 on Day 1 of Period 1. |
| Part 2: Maximum Measured Concentration of BI 1358894 in Plasma After Administration of the Oral Suspension (Cmax) | Within 2 hours (h) before drug administration and at 15 minutes (min), 30 min, 1 h, 1.5, 2, 3, 4, 5, 6, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after administration of BI 1358894. | Maximum measured concentration of BI 1358894 in plasma after administration of the oral suspension (Cmax) is reported. The Analysis of variance (ANOVA) model included effects accounting for the following sources of variation: 'sequence or block', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Standard error is actually geometric standard error. |
| Part 2: Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity After Administration of the Oral Suspension (AUC0-infinity) | Within 2 hours (h) before drug administration and at 15 minutes (min), 30 min, 1 h, 1.5, 2, 3, 4, 5, 6, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after administration of BI 1358894. | Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 extrapolated to infinity after administration of the oral suspension (AUC0-infinity) is reported. The Analysis of variance (ANOVA) model included effects accounting for the following sources of variation: 'sequence or block', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Standard error is actually geometric standard error. |
Countries
Netherlands
Participant flow
Recruitment details
This was a phase I trial which investigated the pharmacokinetics and absolute bioavailability of BI 1358894 administered orally as tablet co-administered with an intravenous microtracer dose of labelled \[C-14\]-BI 1358894 in healthy male volunteers via a non-randomised, open-label, fixed-sequence trial (part 1) followed by a randomised, openlabel, single-dose, two-period, two-sequence cross-over relative bioavailability trial in BI 1358894 oral suspension (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 to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| BI 1358894: Part 1: Tablet (T1) - (C14) i.v (R1), Part 2: Fasted (R2) - Fed (T2) In Part 1: Period 1 of the study participants received on Day 1 one single oral dose of two 50 milligram (mg) BI 1358894 tablets (total dose=100mg) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) (Test 1-T1). 5 hours after the oral administration (i.e. at the time of the expected tmax) participants received one single dose of 10 mL intravenous (i.v) infusion of 100 microgram (µg) BI 1358894 using a mixture of 90 µg unlabelled and 10 µg \[C-14\] labelled BI 1358894 (Reference 1-R1).
After 15 days of washout the Part 2: Period 2 of the study started and participants received on Day 1 of Period 2 one single dose of 100 mg BI 1358894 administered as an oral suspension with 240 mL of water after an overnight fast of at least 10 h when fasted (Reference 2-R2). After 17 days of washout Part 2: Period 3 started and participants received on Day 1 of Period 3 one single dose 100 mg BI 1358894 administered as an oral suspension with 240 mL of water following a high-fat, high-calorie breakfast when fed (Test 2-T2). | 6 |
| BI 1358894: Part 1: Tablet (T1) - (C14) i.v (R1), Part 2: Fed (T2) - Fasted (R2) In Part 1: Period 1 of the study participants received on Day 1 one single oral dose of two 50 milligram (mg) BI 1358894 tablets (total dose=100mg) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) (Test 1-T1). 5 hours after the oral administration (i.e. at the time of the expected tmax) participants received one single dose of 10 mL intravenous (i.v) infusion of 100 microgram (µg) BI 1358894 using a mixture of 90 µg unlabelled and 10 µg \[C-14\] labelled BI 1358894 (Reference 1-R1).
After 15 days of washout Part 2: Period 2 started and participants received on Day 1 of Period 2 one single dose 100 mg BI 1358894 administered as an oral suspension with 240 mL of water following a high-fat, high-calorie breakfast when fed (Test 2-T2). After 17 days of washout the Part 2: Period 3 of the study started and participants received on Day 1 of Period 3 one single dose of 100 mg BI 1358894 administered as an oral suspension with 240 mL of water after an overnight fast of at least 10 h when fasted (Reference 2-R2). | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 2: Period 2+Washout | Adverse Event | 1 | 0 |
| Part 2: Period 2+Washout | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Total | BI 1358894: Part 1: Tablet (T1) - (C14) i.v (R1), Part 2: Fed (T2) - Fasted (R2) | BI 1358894: Part 1: Tablet (T1) - (C14) i.v (R1), Part 2: Fasted (R2) - Fed (T2) |
|---|---|---|---|
| Age, Continuous | 38.5 Years STANDARD_DEVIATION 12.4 | 37.8 Years STANDARD_DEVIATION 14 | 39.2 Years STANDARD_DEVIATION 11.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 6 Participants | 6 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 12 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 6 Participants | 6 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 / 12 | 0 / 12 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 6 / 12 | 9 / 12 | 6 / 11 | 8 / 11 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 11 | 0 / 11 |
Outcome results
Primary
Part 1: Area Under the Concentration-time Curve of BI 1358894 Over the Time Interval From 0 to Infinity After i.v. Administration and After Oral Administration (AUC0-infinity)
Area under the concentration-time curve of BI 1358894 over the time interval from 0 to infinity after i.v. administration and after oral administration (AUC0-infinity) is reported. The values were calculated using the Analysis of variance (ANOVA) model which included effects accounting for the following sources of variation: 'subjects' and 'formulation'. The effect 'subjects' was considered as random, whereas 'formulation' was considered as fixed. Standard error is actually geometric standard error. Time Frame: For BI 1358894 (C-14) 100 ug i.v samples were collected at 5h, 5.083, 5.16, 5.25, 5.5, 5.75, 6, 6.5, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after oral dose of BI 1358894 on Day 1 of Period 1.
Time frame: Within 2 hours (h) before and at 15 minutes (min), 30 min, 1 h, 1.5, 2, 3, 4, 5, 5.083, 5.16, 5.25, 5.5, 5.75, 6, 6.5, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after oral dose of BI 1358894 on Day 1 of Period 1. Continues in description.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the 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. Thus, a subject was included in the PKS even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1358894 100 mg Tablet Fasted | Part 1: Area Under the Concentration-time Curve of BI 1358894 Over the Time Interval From 0 to Infinity After i.v. Administration and After Oral Administration (AUC0-infinity) | 96 hour*millimol/Liter/kilogram |
| BI 1358894 (C-14) 100 ug i.v | Part 1: Area Under the Concentration-time Curve of BI 1358894 Over the Time Interval From 0 to Infinity After i.v. Administration and After Oral Administration (AUC0-infinity) | 209 hour*millimol/Liter/kilogram |
Comparison: The Analysis of variance (ANOVA) model included effects accounting for the following sources of variation: 'subjects' and 'formulation'. The effect 'subjects' was considered as random, whereas 'formulation' was considered as fixed.90% CI: [41.4, 50.9]
Primary
Part 2: Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to 312 h (AUC 0-312)
Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 to 312 h (AUC 0-312) is reported. The values were calculated using the Analysis of variance (ANOVA) model which included effects accounting for the following sources of variation: 'sequence or block', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Standard error is actually geometric standard error.
Time frame: Within 2 hours (h) before drug administration and at 15 minutes (min), 30 min, 1 h, 1.5, 2, 3, 4, 5, 6, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after administration of BI 1358894.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the 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. Thus, a subject was included in the PKS even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. For both arms 11 subjects were treated.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1358894 100 mg Tablet Fasted | Part 2: Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to 312 h (AUC 0-312) | 12217 hour* nanomol/Liter (h*nmol/L) |
| BI 1358894 (C-14) 100 ug i.v | Part 2: Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to 312 h (AUC 0-312) | 17271 hour* nanomol/Liter (h*nmol/L) |
Comparison: The ANOVA model included effects accounting for the following sources of variation: 'sequence or block', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [129.3, 154.6]
Secondary
Part 1: Maximum Measured Concentration of BI 1358894 in Plasma After i.v. Administration and After Oral Administration (Cmax)
Maximum measured concentration of BI 1358894 in plasma after i.v. administration and after oral administration(Cmax) is reported. Time Frame: For BI 1358894 (C-14) 100 ug i.v samples were collected at 5h, 5.083, 5.16, 5.25, 5.5, 5.75, 6, 6.5, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after oral dose of BI 1358894 on Day 1 of Period 1.
Time frame: Within 2 hours before and at 15 minutes (min), 30 min, 1 hour (h), 1.5, 2, 3, 4, 5, 5.083, 5.16, 5.25, 5.5, 5.75, 6, 6.5, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after oral dose of BI 1358894 on Day 1 of Period 1. Continues in description.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the 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. Thus, a subject was included in the PKS even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 1358894 100 mg Tablet Fasted | Part 1: Maximum Measured Concentration of BI 1358894 in Plasma After i.v. Administration and After Oral Administration (Cmax) | 408 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 34.1 |
| BI 1358894 (C-14) 100 ug i.v | Part 1: Maximum Measured Concentration of BI 1358894 in Plasma After i.v. Administration and After Oral Administration (Cmax) | 0.847 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 28.8 |
Secondary
Part 2: Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity After Administration of the Oral Suspension (AUC0-infinity)
Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 extrapolated to infinity after administration of the oral suspension (AUC0-infinity) is reported. The Analysis of variance (ANOVA) model included effects accounting for the following sources of variation: 'sequence or block', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Standard error is actually geometric standard error.
Time frame: Within 2 hours (h) before drug administration and at 15 minutes (min), 30 min, 1 h, 1.5, 2, 3, 4, 5, 6, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after administration of BI 1358894.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the 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. Thus, a subject was included in the PKS even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. For both arms 11 subjects were treated.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1358894 100 mg Tablet Fasted | Part 2: Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity After Administration of the Oral Suspension (AUC0-infinity) | 13510 hour*nanomol/Liter (h*nmol/L) |
| BI 1358894 (C-14) 100 ug i.v | Part 2: Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity After Administration of the Oral Suspension (AUC0-infinity) | 20052 hour*nanomol/Liter (h*nmol/L) |
Comparison: The ANOVA model included effects accounting for the following sources of variation: 'sequence or block', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [138.1, 159.5]
Secondary
Part 2: Maximum Measured Concentration of BI 1358894 in Plasma After Administration of the Oral Suspension (Cmax)
Maximum measured concentration of BI 1358894 in plasma after administration of the oral suspension (Cmax) is reported. The Analysis of variance (ANOVA) model included effects accounting for the following sources of variation: 'sequence or block', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Standard error is actually geometric standard error.
Time frame: Within 2 hours (h) before drug administration and at 15 minutes (min), 30 min, 1 h, 1.5, 2, 3, 4, 5, 6, 7,8, 10, 12, 24, 34, 48, 72, 96, 144, 192, 240, 312 h after administration of BI 1358894.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the 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. Thus, a subject was included in the PKS even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. For both arms 11 subjects were treated.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1358894 100 mg Tablet Fasted | Part 2: Maximum Measured Concentration of BI 1358894 in Plasma After Administration of the Oral Suspension (Cmax) | 810 nanomol/Liter (nmol/L) |
| BI 1358894 (C-14) 100 ug i.v | Part 2: Maximum Measured Concentration of BI 1358894 in Plasma After Administration of the Oral Suspension (Cmax) | 529 nanomol/Liter (nmol/L) |
Comparison: The ANOVA model included effects accounting for the following sources of variation: 'sequence or block', 'subjects within sequences', 'period' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [54.6, 78]