Influence of CYP3A4-induction by St. John's Wort on the Steady State Pharmacokinetics of Bosentan

• Sponsor: Gerd Mikus (Other)
• Overall Status: Completed
• CT.gov ID: NCT01258504
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Duration (Months): 17
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The aim of the present study is to assess the impact of the cytochrome P450 2C9 (CYP2C9) genotype (*2 and *3 allele versus wild type; ~3-5% poor metabolisers in Caucasian population) on the pharmacokinetics of bosentan and the impact of CYP3A4-induction by St. John's wort (SJW) on steady state bosentan which is a CYP3A4 inducer itself.

Condition or Disease	Intervention/Treatment	Phase
Drug Interactions	Drug: St. Johns Wort

Detailed Description

We evaluate the effect of SJW on bosentan pharmacokinetics and its relationship to polymorphisms in the CYP2C9 gene known to reduce CYP2C9 activity. This study will be conducted at bosentan steady-state because concentrations decrease in the first 10 days of treatment due to auto-induction of the metabolism.

Study Design

• Study Type: Observational
• Actual Enrollment: 13 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Influence of Cytochrome P450 3A4 (CYP3A4)-Induction by St. John's Wort (SJW) on the Steady State Pharmacokinetics of Bosentan
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
CYP2C9 wild type CYP2C9 wild type ="extensive metaboliser" Administration of bosentan: 1 x 125 mg p.o. on days 1 and 20, 2 x 62.5 mg p.o. on day 2, 2 x 125 mg p.o. on days 3-19 Administration of St. Johns Wort: 3 x 300 mg daily p.o. on days 11-19 and 2 x 300 mg on day 20	Drug: St. Johns Wort; Administration of bosentan: 1 x 125 mg p.o. on days 1 and 20, 2 x 62.5 mg p.o. on day 2, 2 x 125 mg p.o. on days 3-19. Administration of SJW: 3 x 300 mg daily p.o. on days 11-19 and 2 x 300 mg on day 20; Other Names: Jarsin
CYP2C9 mutant CYP2C9 *2/*2 or 2*/*3 or *3/*3 = "poor metaboliser" Administration of bosentan: 1 x 125 mg p.o. on days 1 and 20, 2 x 62.5 mg p.o. on day 2, 2 x 125 mg p.o. on days 3-19 Administration of St. Johns Wort: 3 x 300 mg daily p.o. on days 11-19 and 2 x 300 mg on day 20	Drug: St. Johns Wort; Administration of bosentan: 1 x 125 mg p.o. on days 1 and 20, 2 x 62.5 mg p.o. on day 2, 2 x 125 mg p.o. on days 3-19. Administration of SJW: 3 x 300 mg daily p.o. on days 11-19 and 2 x 300 mg on day 20; Other Names: Jarsin

Outcome Measures

Primary Outcome Measures

1. AUC of Bosentan [0-infinity; during dosing interval]

2. Cmax of Bosentan [after first dose, at steady-state and during SJW]

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 × upper limit of normal(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 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	69120

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, Head of Clinical Research Unit, Heidelberg University
• ClinicalTrials.gov Identifier: NCT01258504
• Other Study ID Numbers: K330; 2010-022328-64
• First Posted: Dec 13, 2010
• Last Update Posted: May 31, 2017
• Last Verified: May 1, 2017

• Keywords provided by Gerd Mikus, Head of Clinical Research Unit, Heidelberg University: Steady-state; Bosentan; St. Johns Wort

Study Results

Participant Flow

Arm/Group Title	Bosentan
Arm/Group Description	bosentan 125 mg p.o. single dose day 1 bosentan 62.5 mg p.o. b.i.d. day 2-10 bosentan 62.5 mg p.o. b.i.d. day 11-20 SJW 300 mg p.o. t.i.d. day 11-20
Period Title: Bosentan Single Dose
STARTED	13
COMPLETED	13
NOT COMPLETED	0
Period Title: Bosentan Single Dose
STARTED	13
COMPLETED	13
NOT COMPLETED	0
Period Title: Bosentan Single Dose
STARTED	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Bosentan
Arm/Group Description	bosentan 125 mg p.o. day 1 single dose bosentan 62.5 mg p.o. b.i.d. day 2-10 bosentan 62.5 mg p.o. b.i.d. day 11-20 SJW 300 mg p.o. t.i.d. day 11-20
Overall Participants	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35 (11)
Sex: Female, Male (Count of Participants)
Female	1 7.7%
Male	12 92.3%
Region of Enrollment (participants) [Number]
Germany	13 100%

Outcome Measures

1. Primary Outcome

Title	AUC of Bosentan
Time Frame	0-infinity; during dosing interval

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bosentan After First Dose	Bosentan at Steady-state	Bosentan During St John's Wort
Arm/Group Description	bosentan 125 mg p.o. day 1 single dose	bosentan 62.5 mg p.o. b.i.d. day 2-10	bosentan 62.5 mg p.o. b.i.d. day 11-20 SJW 300 mg t.i.d. day 11-20
Measure Participants	13	13	13
Geometric Mean (95% Confidence Interval) [h*ng/ml]	9540	5710	5020

2. Primary Outcome

Title	Cmax of Bosentan
Time Frame	after first dose, at steady-state and during SJW

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bosentan After First Dose	Bosentan at Steady-state	Bosentan During St John's Wort
Arm/Group Description	bosentan125 mg p.o. day 1 single dose	bosentan 62.5 mg p.o. b.i.d. day 2-10	bosentan 62.5 mg p.o. b.i.d. day 11-20 SJW 300 mg t.i.d. day 11-20
Measure Participants	13	13	13
Geometric Mean (95% Confidence Interval) [ng/ml]	1620	1370	1280

Adverse Events

Arm/Group Title	Bosentan After First Dose		Bosentan at Steady-state		Bosentan During St John's Wort
Arm/Group Description	bosentan 125 mg p.o. day 1 single dose		bosentan 62.5 mg p.o. b.i.d. day 2-10		bosentan 62.5 mg p.o. b.i.d. day 11-20 SJW 300 mg t.i.d. day 11-20
All Cause Mortality
	Bosentan After First Dose		Bosentan at Steady-state		Bosentan During St John's Wort
	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 St John's Wort
	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
	Bosentan After First Dose		Bosentan at Steady-state		Bosentan During St John's Wort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/13 (69.2%)		9/13 (69.2%)		4/13 (30.8%)
General disorders
feeling of heat	1/13 (7.7%)		0/13 (0%)		0/13 (0%)
headache	4/13 (30.8%)		4/13 (30.8%)		1/13 (7.7%)
dyspnea	1/13 (7.7%)		0/13 (0%)		0/13 (0%)
increase of alanine aminotransferase	1/13 (7.7%)		1/13 (7.7%)		0/13 (0%)
pressure sensation in the head	1/13 (7.7%)		1/13 (7.7%)		0/13 (0%)
epigastric pressure sensation	1/13 (7.7%)		1/13 (7.7%)		0/13 (0%)
nasopharyngitis	1/13 (7.7%)		1/13 (7.7%)		2/13 (15.4%)
nausea	1/13 (7.7%)		1/13 (7.7%)		0/13 (0%)
strained muscle	1/13 (7.7%)		1/13 (7.7%)		0/13 (0%)
nasal congestion	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
ocular itching with secretion of tears	0/13 (0%)		0/13 (0%)		1/13 (7.7%)

Limitations/Caveats

Interindividual changes of the interaction were large suggesting that close monitoring of bosentan effects is advisable because in a sizeable fraction of volunteers the exposure to bosentan was reduced.

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.