Healthy
Conditions
Brief summary
The primary objective of this trial is to investigate the absolute bioavailability of BI 409306. The secondary objective is the evaluation and comparison of several pharmacokinetic parameters for the different treatments.
Interventions
DRUGBI 409306 (C-13/N-15)
i.v solution
DRUGBI 409306
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, 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 (incl.) * BMI of 18.5 to 29.9 kg/m2 (incl.) * Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation * Known CYP 2C19 metabolizer status * Male subjects, or female subjects who meet any of the following criteria starting from at least 30 days before the first administration of trial medication and until 30 days after trial completion: * Use of adequate contraception, e.g. non-hormonal intrauterine device plus condom. * Sexually abstinent * 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 simultaneous levels of 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) is deviating from normal and judged 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 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and 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 * Chronic or relevant acute infections * History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients) * Use of drugs within 30 days prior to administration of trial medication if that might reasonably influence the results of the trial (incl. QT/QTc interval prolongation) * Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication, or current participation in another trial involving administration of investigational drug * Current smoker or ex-smoker who quit smoking less than 30 days prior to screening * Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for males) * Drug abuse or positive drug screening * Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial * Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial * Inability to comply with dietary regimen of trial site * A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 msec in males or repeatedly greater than 470 msec in females) or any other relevant ECG finding at screening * A history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalemia, or family history of Long QT Syndrome) * Subject is assessed as unsuitable for inclusion by the investigator, for instance, because considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study Female subjects will not be allowed to participate if any of the following applies: * Positive pregnancy test, pregnancy or plans to become pregnant within 30 days after study completion * Lactation period * Concomitant use of hormonal replacement therapy or hormonal contraceptives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h. | Area under the concentration-time curve of BI 409306 and stable labelled isotope BI 409306 (C-13/N-15) over the time interval from 0 extrapolated to infinity (AUC0-∞). The dose-normalized values for AUC0-∞ are reported. |
| Maximum Measured Concentration of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15), (Cmax) | T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h. | Maximum measured concentration of the analyte BI 409306 and stable labelled isotope BI 409306 (C-13/N-15), (Cmax). The dose-normalized values for Cmax are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| For: BI 409306 (C-13/N-15): Total Clearance (CL) of BI 409306 (C-13/N-15) | Within 3 hours (h) before drug administration, 0.58h, 0.75h, 0.83h, 0.97h, 1.17h, 1.333h, 1.5h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. | Total clearance (CL) of BI 409306 (C-13/N-15) is reported. |
| Terminal Half-life of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) in Plasma (t1/2) | T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h. | Terminal half-life of BI 409306 and stable labelled isotope BI 409306 (C-13/N-15) in plasma (t1/2) is reported. |
| Absolute Bioavailability of BI 409306 (Fabs) | T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h. | The evaluation of the absolute bioavailability (Fabs) of BI 409306 was performed by calculating the ratio between the area under the concentration-time curve over the time interval from 0 extrapolated to infinity (AUC0-∞) determined for the oral treatment (T) and the (AUC0-∞) determined for the i.v. infusion (R), corrected by the respective dose, and multiplied by 100. |
| For BI 409306 (C-13/N-15): Apparent Volume of Distribution During the Terminal Phase After Intravascular Administration (Vz) of BI 409306 (C-13/N-15) | Within 3 hours (h) before drug administration, 0.58h, 0.75h, 0.83h, 0.97h, 1.17h, 1.333h, 1.5h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. | Apparent volume of distribution during the terminal phase after intravascular administration of BI 409306 (C-13/N-15) is reported. |
| Time From Dosing to Maximum Measured Concentration of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) in Plasma (Tmax) | T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h. | Time from dosing to maximum measured concentration of BI 409306 and stable labelled isotope BI 409306 (C-13/N-15) in plasma is reported. |
Countries
Germany
Participant flow
Recruitment details
The study was a non-randomized, open-label, single arm, single period, phase 1 clinical trial in healthy subjects in order to compare the reference treatment (R) which consisted of an infusion of 0.1 mg intravenously administered stable labeled isotope BI 409306 (C-13/N-15); with 50 mg of orally administered unlabeled BI 409306 (Test treatment, T).
Pre-assignment details
All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be entered to trial drug if any of the specific entry criteria was violated.
Participants by arm
| Arm | Count |
|---|---|
| BI 409306 Tablet + Intravenous Isotope BI 409306 (C-13/N-15) On day 1, subjects were administered the Test treatment (T): a single dose of 50 milligram (mg) of BI 409306 film-coated tablet orally with 240 milliliter (mL) of water, followed 30 minutes (min) later by the Reference treatment (R): 0.1 mg isotope BI 409306 (C-13/N-15) as intravenous (i.v.) infusion over 30 minutes.
Both treatments were given in fasted state. | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | BI 409306 Tablet + Intravenous Isotope BI 409306 (C-13/N-15) |
|---|---|
| Age, Continuous | 38.8 Years STANDARD_DEVIATION 11.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 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 | 9 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 5 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
Primary
Area Under the Concentration-time Curve of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of BI 409306 and stable labelled isotope BI 409306 (C-13/N-15) over the time interval from 0 extrapolated to infinity (AUC0-∞). The dose-normalized values for AUC0-∞ are reported.
Time frame: T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h.
Population: Pharmacokinetic Set (PKS). The PKS included all subjects from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK or due to non-evaluability.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Test Treatment (T): BI 409306 | Area Under the Concentration-time Curve of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | NA millimole*hour/L/kg [mmol*h/L/kg] |
| Reference Treatment (R): BI 409306 C-13/N-15 | Area Under the Concentration-time Curve of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | NA millimole*hour/L/kg [mmol*h/L/kg] |
Comparison: Absolute bioavailability was evaluated using an Analysis of variance model (ANOVA) on BI 409306 AUC0-inf versus 0.1 mg BI 409306 C-13/N-15 i.v. This 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. The dose normalised PK endpoints were log transformed (natural logarithm) prior to fitting the ANOVA model.90% CI: [32.62, 61.06]
Primary
Maximum Measured Concentration of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15), (Cmax)
Maximum measured concentration of the analyte BI 409306 and stable labelled isotope BI 409306 (C-13/N-15), (Cmax). The dose-normalized values for Cmax are reported.
Time frame: T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h.
Population: Pharmacokinetic Set (PKS). The PKS included all subjects from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK or due to non-evaluability.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Test Treatment (T): BI 409306 | Maximum Measured Concentration of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15), (Cmax) | NA picomole/Liter/microgram [pmol/L/μg] |
| Reference Treatment (R): BI 409306 C-13/N-15 | Maximum Measured Concentration of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15), (Cmax) | NA picomole/Liter/microgram [pmol/L/μg] |
Comparison: Ratios of BI 409306 for Cmax versus 0.1 mg BI 409306 C-13/N-15 i.v. was evaluated using ANOVA model. This 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. The dose normalised PK endpoints were log transformed (natural logarithm) prior to fitting the ANOVA model.90% CI: [27.38, 81.55]
Secondary
Absolute Bioavailability of BI 409306 (Fabs)
The evaluation of the absolute bioavailability (Fabs) of BI 409306 was performed by calculating the ratio between the area under the concentration-time curve over the time interval from 0 extrapolated to infinity (AUC0-∞) determined for the oral treatment (T) and the (AUC0-∞) determined for the i.v. infusion (R), corrected by the respective dose, and multiplied by 100.
Time frame: T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h.
Population: Pharmacokinetic Set (PKS). The PKS included all subjects from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK or due to non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T): BI 409306 | Absolute Bioavailability of BI 409306 (Fabs) | 44.6 % of bioavailability | Geometric Coefficient of Variation 54 |
Secondary
For BI 409306 (C-13/N-15): Apparent Volume of Distribution During the Terminal Phase After Intravascular Administration (Vz) of BI 409306 (C-13/N-15)
Apparent volume of distribution during the terminal phase after intravascular administration of BI 409306 (C-13/N-15) is reported.
Time frame: Within 3 hours (h) before drug administration, 0.58h, 0.75h, 0.83h, 0.97h, 1.17h, 1.333h, 1.5h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing.
Population: Pharmacokinetic Set (PKS). The PKS included all subjects from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK or due to non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T): BI 409306 | For BI 409306 (C-13/N-15): Apparent Volume of Distribution During the Terminal Phase After Intravascular Administration (Vz) of BI 409306 (C-13/N-15) | 98.9 Liter (L) | Geometric Coefficient of Variation 21.5 |
Secondary
For: BI 409306 (C-13/N-15): Total Clearance (CL) of BI 409306 (C-13/N-15)
Total clearance (CL) of BI 409306 (C-13/N-15) is reported.
Time frame: Within 3 hours (h) before drug administration, 0.58h, 0.75h, 0.83h, 0.97h, 1.17h, 1.333h, 1.5h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing.
Population: Pharmacokinetic Set (PKS). The PKS included all subjects from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK or due to non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T): BI 409306 | For: BI 409306 (C-13/N-15): Total Clearance (CL) of BI 409306 (C-13/N-15) | 825 milliliter/minute (mL/min) | Geometric Coefficient of Variation 33.6 |
Secondary
Terminal Half-life of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) in Plasma (t1/2)
Terminal half-life of BI 409306 and stable labelled isotope BI 409306 (C-13/N-15) in plasma (t1/2) is reported.
Time frame: T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h.
Population: Pharmacokinetic Set (PKS). The PKS included all subjects from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK or due to non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T): BI 409306 | Terminal Half-life of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) in Plasma (t1/2) | 1.49 hour (h) | Geometric Coefficient of Variation 23.1 |
| Reference Treatment (R): BI 409306 C-13/N-15 | Terminal Half-life of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) in Plasma (t1/2) | 1.39 hour (h) | Geometric Coefficient of Variation 24.3 |
Secondary
Time From Dosing to Maximum Measured Concentration of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) in Plasma (Tmax)
Time from dosing to maximum measured concentration of BI 409306 and stable labelled isotope BI 409306 (C-13/N-15) in plasma is reported.
Time frame: T and R:Within 3 hours (h) before dosing, 0.75h, 0.97h, 1.333h, 1.75h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h after dosing. Only T: 0.17h, 0.333h, 0.47h. Only R:0.58h, 0.83h, 1.17h, 1.5h.
Population: Pharmacokinetic Set (PKS). The PKS included all subjects from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK or due to non-evaluability.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Test Treatment (T): BI 409306 | Time From Dosing to Maximum Measured Concentration of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) in Plasma (Tmax) | 0.333 hour (h) |
| Reference Treatment (R): BI 409306 C-13/N-15 | Time From Dosing to Maximum Measured Concentration of BI 409306 and Stable Labelled Isotope BI 409306 (C-13/N-15) in Plasma (Tmax) | 0.467 hour (h) |