Influence of Bosentan on the Pharmacokinetics of Nintedanib

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02667704
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arms: 2
• Duration (Days): 29
• Patients Per Site Per Month: 13.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Bosentan; Drug: Nintedanib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Influence of Bosentan on the Pharmacokinetics of Nintedanib in Healthy Male Subjects
• Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Mar 1, 2016
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nintedanib	Drug: Nintedanib
Experimental: Bosentan	Drug: Bosentan

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boehringer Ingelheim Investigational Site	Biberach		Germany

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02667704
• Other Study ID Numbers: 1199.239; 2015-003819-38
• First Posted: Jan 29, 2016
• Last Update Posted: Apr 13, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Nintedanib; Bosentan

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Nintedanib (Reference (R)) / Bosentan+Nintedanib (Test (T))
Arm/Group Description	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
Period Title: Treatment Period 1
STARTED	13
COMPLETED	13
NOT COMPLETED	0
Period Title: Treatment Period 1
STARTED	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Nintedanib (Reference (R)) / Bosentan+Nintedanib (Test (T))
Arm/Group Description	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
Overall Participants	13
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	35.0 (9.8)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	13 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Concentration (AUC0-tz)
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.
Time Frame	Up to 216 hours. The details are mentioned in description.

Outcome Measure Data

Analysis Population Description

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/Group Title	Nintedanib (R)	Bosentan+Nintedanib (T)
Arm/Group Description	Subject received single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 1 administered orally with 240 millilitre (mL) of water.	Subject received multiple doses of 250 mg Bosentan (2 x 1 film-coated tablets) on days 1 to 8 plus single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 7 administered orally with 240 mL of water
Measure Participants	13	13
Geometric Mean (Geometric Coefficient of Variation) [nanogram (ng)*hour (h) /millilitre (mL)]	195 (38.8)	193 (33.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib (R), Bosentan+Nintedanib (T)
	Comments	Analysis of variance (ANOVA) model on the log scale including treatment as fixed effect and subject as a random effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means in percentage
	Estimated Value	98.85
	Confidence Interval	(2-Sided) 90%; 91.320 to 107.010
	Parameter Dispersion	Type: Standard Deviation; Value: 11.4
	Estimation Comments	Relative bioavailability was estimated by the ratio (T/R) of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient of variation.

2. Primary Outcome

Title	Maximum Measured Concentration of Nintedanib in Plasma (Cmax)
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.
Time Frame	Up to 216 hours. The details are mentioned in description.

Outcome Measure Data

Analysis Population Description

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/Group Title	Nintedanib (R)	Bosentan+Nintedanib (T)
Arm/Group Description	Subject received single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 1 administered orally with 240 millilitre (mL) of water.	Subject received multiple doses of 250 mg Bosentan (2 x 1 film-coated tablets) on days 1 to 8 plus single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 7 administered orally with 240 mL of water
Measure Participants	13	13
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	21.9 (55.2)	22.7 (42.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib (R), Bosentan+Nintedanib (T)
	Comments	Analysis of variance (ANOVA) model on the log scale including treatment as fixed effect and subject as a random effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means in percentage
	Estimated Value	103.36
	Confidence Interval	(2-Sided) 90%; 86.134 to 124.025
	Parameter Dispersion	Type: Standard Deviation; Value: 26.5
	Estimation Comments	Relative bioavailability was estimated by the ratio (T/R) of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient of variation.

3. Secondary Outcome

Title	Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity)
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.
Time Frame	Up to 216 hours. The details are mentioned in description.

Outcome Measure Data

Analysis Population Description

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/Group Title	Nintedanib (R)	Bosentan+Nintedanib (T)
Arm/Group Description	Subject received single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 1 administered orally with 240 millilitre (mL) of water.	Subject received multiple doses of 250 mg Bosentan (2 x 1 film-coated tablets) on days 1 to 8 plus single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 7 administered orally with 240 mL of water
Measure Participants	13	13
Geometric Mean (Geometric Coefficient of Variation) [ng*h / mL]	204 (38.3)	208 (34.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib (R), Bosentan+Nintedanib (T)
	Comments	Analysis of variance (ANOVA) model on the log scale including treatment as fixed effect and subject as a random effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means in percentage
	Estimated Value	101.98
	Confidence Interval	(2-Sided) 90%; 94.909 to 109.570
	Parameter Dispersion	Type: Standard Deviation; Value: 10.3
	Estimation Comments	Relative bioavailability was estimated by the ratio (T/R) of the adjusted geometric means (gMean). Standard deviation is actually Intra individual geometric coefficient of variation.

Adverse Events

Time Frame	From first drug administration until 13 days after the last drug administration, up to 21 days
Arm/Group Title	Nintedanib (R)		Bosentan		Bosentan+Nintedanib (T)
Arm/Group Description	Subject received single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 1 of period 1 administered orally with 240 millilitre (mL) of water.		Subject received multiple doses of 250 mg Bosentan (2 x 1 film-coated tablets) on days 1 to 6 of period 2 administered orally with 240 mL of water		Subject received multiple doses of 250 mg Bosentan (2 x 1 film-coated tablets) on days 7 and 8 of period 2 plus single dose of 150 milligram (mg) Nintedanib (1 x 1 soft gelatin capsule) on day 7 administered orally with 240 mL of water
All Cause Mortality
	Nintedanib (R)		Bosentan		Bosentan+Nintedanib (T)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Nintedanib (R)		Bosentan		Bosentan+Nintedanib (T)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Nintedanib (R)		Bosentan		Bosentan+Nintedanib (T)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/13 (30.8%)		4/13 (30.8%)		2/13 (15.4%)
Gastrointestinal disorders
Diarrhoea	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Infections and infestations
Herpes simplex	0/13 (0%)		1/13 (7.7%)		0/13 (0%)
Oral herpes	1/13 (7.7%)		0/13 (0%)		0/13 (0%)
Rhinitis	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Nervous system disorders
Dizziness	1/13 (7.7%)		0/13 (0%)		0/13 (0%)
Headache	2/13 (15.4%)		1/13 (7.7%)		0/13 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/13 (0%)		1/13 (7.7%)		0/13 (0%)
Skin and subcutaneous tissue disorders
Dry skin	0/13 (0%)		1/13 (7.7%)		0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.