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

NCT ID: NCT01258504

Last Updated: 2017-05-31

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 13 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2011-01-31
• Study Completion Date: 2012-06-30

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.

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.

Conditions

Drug Interactions

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

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

St. Johns Wort

Intervention Type: DRUG

• 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

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

St. Johns Wort

Intervention Type: DRUG

• 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

Interventions

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

Intervention Type: DRUG

Other Intervention Names

Jarsin

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Gerd Mikus

OTHER

Sponsor Role: lead

Responsible Party

Gerd Mikus

Head of Clinical Research Unit

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Gerd Mikus, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

deputy head of department

Locations

University Hospital Heidelberg

Heidelberg, , Germany

Countries

Germany

References

Dingemanse J, van Giersbergen PL. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089-115. doi: 10.2165/00003088-200443150-00003.

Reference Type: BACKGROUND

PMID: 15568889 (View on PubMed)

Other Identifiers

2010-022328-64

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

K330

Identifier Type: -

Identifier Source: org_study_id