Healthy
Conditions
Brief summary
The trial was designed to investigate whether, and to which extent, multiple doses of bosentan may influence the plasma levels of nintedanib administered as a single dose.
Interventions
DRUGBosentan
DRUGNintedanib
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
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 investigators assessment, 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 * Males who are willing to use a medically acceptable method of contraception during the study (from start of treatment until end of trial examination). Acceptable methods of contraception for use by male volunteers include sexual abstinence, a vasectomy performed at least 1 year prior to dosing, and barrier contraception (condom). Subjects, who are not vasectomised or sexually abstinent have to ensure that an additional acceptable method of contraception will be used by his female partner such as IUD (intrauterine device), surgical sterilisation (including hysterectomy), hormonal contraception (e.g. implants, injectables, combined oral or vaginal contraceptives) that started at least 2 months prior to first nintedanib administration, or barrier method (e.g. diaphragm with spermicide).
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) * Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication * Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial * Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication * Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) * Inability to refrain from smoking on specified trial days * Alcohol abuse (consumption of more than 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 * 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 * Laboratory parameters ALT, AST or GGT outside the reference range * Intake of drugs that inhibit the efflux of bile salts (e.g. rifampicin, glibenclamide, cyclosporine) within 30 days prior to administration of trial medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Concentration (AUC0-tz) | Up to 216 hours. The details are mentioned in description. | Area under the concentration-time curve of Nintedanib in plasma over the time interval from 0 to the last quantifiable concentration (AUC0-tz). PK plasma samples were taken at: 1 hour (h) before drug administration (approximate time for predose sample) and 30 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 144.5h, 145h, 145.5h, 146h, 146.5h, 147h, 148h, 149h, 150h, 152h, 154h, 156h, 168h, 180h, 192h, 216h after drug administration. Two different visits; Visit 2 (R): -1 to 72 h, Visit 3 (T) 144 to 216 h. AUC0-tz was calculated for each visit separately. |
| Maximum Measured Concentration of Nintedanib in Plasma (Cmax) | Up to 216 hours. The details are mentioned in description. | Maximum measured concentration of Nintedanib in plasma (Cmax). PK plasma samples were taken at: 1 hour (h) before drug administration and 30 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 144.5h, 145h, 145.5h, 146h, 146.5h, 147h, 148h, 149h, 150h, 152h, 154h, 156h, 168h, 180h, 192h, 216h after drug administration. Two different visits; Visit 2 (R): -1 to 72 h, Visit 3 (T) 144 to 216 h. Cmax was determined for each visit separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity) | Up to 216 hours. The details are mentioned in description. | Area under the concentration-time curve of Nintedanib in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity). PK plasma samples were taken at: 1 hour (h) before drug administration and 30 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 144.5h, 145h, 145.5h, 146h, 146.5h, 147h, 148h, 149h, 150h, 152h, 154h, 156h, 168h, 180h, 192h, 216h after drug administration. Two different visits; Visit 2 (R): -1 to 72 h, Visit 3 (T) 144 to 216 h. AUC0-infinity was calculated for each visit separately. |
Countries
Germany
Participant flow
Pre-assignment details
This is open-label, mono-center clinical trial in healthy male subjects applied a fixed sequence, two-treatment, two- period crossover design. All subjects were to undergo 2 trial periods in a fixed sequence, receiving reference treatment (R) in Period 1, and test treatment (T) in Period 2. A wash-out between Periods 1 and 2 was not mandatory.
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib (Reference (R)) / Bosentan+Nintedanib (Test (T)) Subject received single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 1 of period 1 and then multiple doses of 250 mg Bosentan (2 x 1 film-coated tablets) on days 1 to 8 of period 2 plus single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 7 of period 2 administered orally with 240 millilitre (mL) of water | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Nintedanib (Reference (R)) / Bosentan+Nintedanib (Test (T)) |
|---|---|
| Age, Continuous | 35.0 Years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 13 | 4 / 13 | 2 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 | 0 / 13 |
Outcome results
Primary
Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Concentration (AUC0-tz)
Area under the concentration-time curve of Nintedanib in plasma over the time interval from 0 to the last quantifiable concentration (AUC0-tz). PK plasma samples were taken at: 1 hour (h) before drug administration (approximate time for predose sample) and 30 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 144.5h, 145h, 145.5h, 146h, 146.5h, 147h, 148h, 149h, 150h, 152h, 154h, 156h, 168h, 180h, 192h, 216h after drug administration. Two different visits; Visit 2 (R): -1 to 72 h, Visit 3 (T) 144 to 216 h. AUC0-tz was calculated for each visit separately.
Time frame: Up to 216 hours. The details are mentioned in description.
Population: Pharmacokinetic parameter analysis set (PKS): all subjects in the treated set who provided at least one primary or secondary pharmacokinetic (PK) parameter not flagged for exclusion due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib (R) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Concentration (AUC0-tz) | 195 nanogram (ng)*hour (h) /millilitre (mL) | Geometric Coefficient of Variation 38.8 |
| Bosentan+Nintedanib (T) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Concentration (AUC0-tz) | 193 nanogram (ng)*hour (h) /millilitre (mL) | Geometric Coefficient of Variation 33.4 |
Comparison: Analysis of variance (ANOVA) model on the log scale including treatment as fixed effect and subject as a random effect90% CI: [91.32, 107.01]ANOVA
Primary
Maximum Measured Concentration of Nintedanib in Plasma (Cmax)
Maximum measured concentration of Nintedanib in plasma (Cmax). PK plasma samples were taken at: 1 hour (h) before drug administration and 30 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 144.5h, 145h, 145.5h, 146h, 146.5h, 147h, 148h, 149h, 150h, 152h, 154h, 156h, 168h, 180h, 192h, 216h after drug administration. Two different visits; Visit 2 (R): -1 to 72 h, Visit 3 (T) 144 to 216 h. Cmax was determined for each visit separately.
Time frame: Up to 216 hours. The details are mentioned in description.
Population: Pharmacokinetic parameter analysis set (PKS): all subjects in the treated set who provided at least one primary or secondary pharmacokinetic (PK) parameter not flagged for exclusion due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib (R) | Maximum Measured Concentration of Nintedanib in Plasma (Cmax) | 21.9 ng/mL | Geometric Coefficient of Variation 55.2 |
| Bosentan+Nintedanib (T) | Maximum Measured Concentration of Nintedanib in Plasma (Cmax) | 22.7 ng/mL | Geometric Coefficient of Variation 42.2 |
Comparison: Analysis of variance (ANOVA) model on the log scale including treatment as fixed effect and subject as a random effect90% CI: [86.134, 124.025]ANOVA
Secondary
Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity)
Area under the concentration-time curve of Nintedanib in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity). PK plasma samples were taken at: 1 hour (h) before drug administration and 30 minutes, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 144h, 144.5h, 145h, 145.5h, 146h, 146.5h, 147h, 148h, 149h, 150h, 152h, 154h, 156h, 168h, 180h, 192h, 216h after drug administration. Two different visits; Visit 2 (R): -1 to 72 h, Visit 3 (T) 144 to 216 h. AUC0-infinity was calculated for each visit separately.
Time frame: Up to 216 hours. The details are mentioned in description.
Population: Pharmacokinetic parameter analysis set (PKS): all subjects in the treated set who provided at least one primary or secondary pharmacokinetic (PK) parameter not flagged for exclusion due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib (R) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity) | 204 ng*h / mL | Geometric Coefficient of Variation 38.3 |
| Bosentan+Nintedanib (T) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity) | 208 ng*h / mL | Geometric Coefficient of Variation 34.1 |
Comparison: Analysis of variance (ANOVA) model on the log scale including treatment as fixed effect and subject as a random effect90% CI: [94.909, 109.57]ANOVA