Influence of OATP1B1 and CYP2C9 Genotypes on the Pharmacokinetics of Bosentan Before and During Clarithromycin

• Sponsor: Gerd Mikus (Other)
• Overall Status: Completed
• CT.gov ID: NCT01425229
• Collaborator: (none)
• Enrollment: 16
• Location: 1
• Duration (Months): 18
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The aim of the present study is to assess the impact of the OATP1B1 genotype (SLCO1B115 vs. wild type; ~2% SLCO1B115 haplotypes in Caucasian population) and the CYP2C9 genotype (*2 and *3 allele vs. wild type; ~5% poor metabolisers in Caucasian population) on the pharmacokinetics of bosentan and the impact of CYP3A4-inhibition by clarithromycin on steady state bosentan which is a CYP3A4 inducer itself.

This study will focus on differential effects of genotypes and co-medication on the pharmacokinetics of bosentan at the metabolic and transport level. Participants will be genotyped for CYP2C9 (inclusion criterion), OATP1B1 (inclusion criterion), and CYP3A5 (no inclusion criterion).

Condition or Disease	Intervention/Treatment	Phase
Drug Interactions	Drug: Bosentan

Study Design

• Study Type: Observational
• Actual Enrollment: 16 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Influence of OATP1B1 and CYP2C9 Genotypes on the Pharmacokinetics of Steady State Bosentan Before and During CYP3A4-inhibition by Clarithromycin
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Bosentan Haplotypes of CYP2C9 and OATP1B1 characterisation of CYP2C9 (CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910)) and OATP1B1 (SLCO1B1*15 (rs2306283, rs4149056))	Drug: Bosentan; Administration of bosentan: 1 x 125 mg p.o. on day 1, 2 x 125 mg p.o. on day 2-14 Administration of clarithromycin: 2 x 500 mg p.o. on day 11-14; Other Names: Tracleer

Outcome Measures

Primary Outcome Measures

1. AUC [0-infinity; dosing interval]

   AUC of bosentan after first-dose, at steady-state and during clarithromycin therapy

2. Cmax [after first dose, at steady-state, during clarithromycin]

   Cmax after the first dose of bosentan, at steady-state, during clarithromycin

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Good state of health (physically and mentally)

• Able to communicate well with the investigator, to understand and comply with the requirements of the study

• Voluntarily signed informed consent after full explanation of the study to the participant.

• No clinically relevant findings in any of the investigations of the pre-study examination, especially aminotransferase elevations ≥ 3 × ULN. Minor deviations of other laboratory values from normal range may be acceptable, if judged by the investigator to be of no clinical relevance.

• Known genotype for CYP2C9 and OATP1B1 polymorphism.

• Agreement to abstain from alcoholic beverages during the time of the study.

• Females must agree to use a reliable contraception (Pearl Index <1%), e.g. double barrier method.

Exclusion Criteria:

• Any regular drug treatment within the last two months, except for oral contraceptives in female volunteers and L-thyroxine.

• Any intake of a substance known to induce or inhibit drug metabolising enzymes or drug transporters within a period of less than 10 times the respective elimination half-life or 2 weeks, whatever is longer

• Any participation in a clinical trial within the last month before inclusion

• Any physical disorder which could interfere with the participant's safety during the clinical trial or with the study objectives

• Any acute or chronic illness, or clinically relevant findings in the pre-study examination, especially: a) any condition, which could modify absorption, distribution, metabolism, or excretion of the drug regimen under investigation b) Allergies (except for mild forms of hay fever) or history of hypersensitivity reactions

• Regular smoking

• Blood donation within 6 weeks before first study day

• Excessive alcohol drinking (more than approximately 20 g alcohol per day)

• Inability to communicate well with the investigator due to language problems or poor mental development

• Inability or unwillingness to give written informed consent

• Known or planned pregnancy or breast feeding

• Pre-existing moderate or severe liver impairment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital Heidelberg	Heidelberg		Germany

Sponsors and Collaborators

• Gerd Mikus

Investigators

• Principal Investigator: Gerd Mikus, Prof. Dr., deputy head of department

Study Documents (Full-Text)

None provided.

More Information

Publications

• Dingemanse J, van Giersbergen PL. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089-115. Review.

• Responsible Party: Gerd Mikus, Prof. Dr. med. Gerd Mikus, Heidelberg University
• ClinicalTrials.gov Identifier: NCT01425229
• Other Study ID Numbers: K318; 2010-021392-93
• First Posted: Aug 29, 2011
• Last Update Posted: May 31, 2017
• Last Verified: May 1, 2017

• Keywords provided by Gerd Mikus, Prof. Dr. med. Gerd Mikus, Heidelberg University: steady state; bosentan; clarithromycin
• Additional relevant MeSH terms: Bosentan

Study Results

Participant Flow

Arm/Group Title	Bosentan
Arm/Group Description	Bosentan pharmacokinetics
Period Title: Bosentan Single Dose
STARTED	16
COMPLETED	16
NOT COMPLETED	0
Period Title: Bosentan Single Dose
STARTED	16
COMPLETED	16
NOT COMPLETED	0
Period Title: Bosentan Single Dose
STARTED	16
COMPLETED	16
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Bosentan
Arm/Group Description	Bosentan PK
Overall Participants	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.6 (7.8)
Sex: Female, Male (Count of Participants)
Female	6 37.5%
Male	10 62.5%
Region of Enrollment (participants) [Number]
Germany	16 100%

Outcome Measures

1. Primary Outcome

Title	AUC
Description	AUC of bosentan after first-dose, at steady-state and during clarithromycin therapy
Time Frame	0-infinity; dosing interval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bosentan After First Dose	Bosentan at Steady-state	Bosentan During Clarithromycin
Arm/Group Description	administration of bosentan 125 mg p.o. single dose	administration of bosentan 125 mg p.o. b.i.d. on day 2-10	administration of bosentan 125 mg p.o. b.i.d. on day 11-14 and administration of clarithromycin 500 mg p.o b.i.d. on day 11-14
Measure Participants	16	16	16
Geometric Mean (95% Confidence Interval) [h*ng/ml]	11900	6830	25500

2. Primary Outcome

Title	Cmax
Description	Cmax after the first dose of bosentan, at steady-state, during clarithromycin
Time Frame	after first dose, at steady-state, during clarithromycin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bosentan After First Dose	Bosentan at Steady-state	Bosentan During Clarithromycin
Arm/Group Description	administration of bosentan 125 mg p.o. single dose	administration of bosentan 125 mg p.o. b.i.d. on day 2-10	administration of bosentan 125 mg p.o. b.i.d. on day 11-14 and administration of clarithromycin 500 mg p.o b.i.d. on day 11-14
Measure Participants	16	16	16
Geometric Mean (95% Confidence Interval) [ng/ml]	1890	1460	5570

Adverse Events

Arm/Group Title	Bosentan After First Dose		Bosentan at Steady-state		Bosentan During Clarithromycin
Arm/Group Description	Bosentan PK after first dose		Bosentan PK at steady-state		Bosentan PK during clarithromycin
All Cause Mortality
	Bosentan After First Dose		Bosentan at Steady-state		Bosentan During Clarithromycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Bosentan After First Dose		Bosentan at Steady-state		Bosentan During Clarithromycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Bosentan After First Dose		Bosentan at Steady-state		Bosentan During Clarithromycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/16 (56.3%)		9/16 (56.3%)		9/16 (56.3%)
Gastrointestinal disorders
Xerostomia	0/16 (0%)		0/16 (0%)		1/16 (6.3%)
Loss of apetite	1/16 (6.3%)		1/16 (6.3%)		0/16 (0%)
Nausea	1/16 (6.3%)		1/16 (6.3%)		0/16 (0%)
Flatulence	1/16 (6.3%)		1/16 (6.3%)		0/16 (0%)
Epigastric pain	1/16 (6.3%)		1/16 (6.3%)		1/16 (6.3%)
Diarrhoea	1/16 (6.3%)		1/16 (6.3%)		2/16 (12.5%)
abdominal pain	0/16 (0%)		0/16 (0%)		1/16 (6.3%)
General disorders
Nasopharyngitis	3/16 (18.8%)		3/16 (18.8%)		2/16 (12.5%)
Nasal congestion	4/16 (25%)		4/16 (25%)		1/16 (6.3%)
Headache	5/16 (31.3%)		4/16 (25%)		5/16 (31.3%)
Night sweats	1/16 (6.3%)		1/16 (6.3%)		0/16 (0%)
Dizziness	1/16 (6.3%)		1/16 (6.3%)		2/16 (12.5%)
Fatigue	1/16 (6.3%)		1/16 (6.3%)		1/16 (6.3%)
taste disorder	0/16 (0%)		0/16 (0%)		1/16 (6.3%)
concentration difficulty	0/16 (0%)		0/16 (0%)		1/16 (6.3%)
tinnitus	0/16 (0%)		0/16 (0%)		1/16 (6.3%)
Investigations
increase of creatinine kinase	0/16 (0%)		0/16 (0%)		1/16 (6.3%)
Increase of aspartate transaminase	0/16 (0%)		0/16 (0%)		1/16 (6.3%)
Tachykardia	0/16 (0%)		0/16 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Eczema	1/16 (6.3%)		1/16 (6.3%)		1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.