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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gerd Mikus, Heidelberg University
ClinicalTrials.gov Identifier:
NCT01258504
First received: December 10, 2010
Last updated: May 29, 2015
Last verified: May 2015
  Purpose

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 Intervention
VA Drug Interactions [VA Drug Interaction]
Drug: St. Johns Wort

Study Type: Observational
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Heidelberg University:

Primary Outcome Measures:
  • AUC of Bosentan [ Time Frame: 0-infinity; during dosing interval ] [ Designated as safety issue: No ]
  • Cmax of Bosentan [ Time Frame: after first dose, at steady-state and during SJW ] [ Designated as safety issue: No ]

Enrollment: 13
Study Start Date: January 2011
Study Completion Date: June 2012
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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 Name: 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 Name: Jarsin

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

healthy subjects

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01258504

Locations
Germany
University Hospital Heidelberg
Heidelberg, Germany, 69120
Sponsors and Collaborators
Gerd Mikus
Investigators
Principal Investigator: Gerd Mikus, Prof. Dr. deputy head of department
  More Information

Publications:
Responsible Party: Gerd Mikus, Head of Clinical Research Unit, Heidelberg University
ClinicalTrials.gov Identifier: NCT01258504     History of Changes
Other Study ID Numbers: K330, 2010-022328-64
Study First Received: December 10, 2010
Results First Received: July 9, 2014
Last Updated: May 29, 2015
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Heidelberg University:
Steady-state
Bosentan
St. Johns Wort

Additional relevant MeSH terms:
Bosentan
Antihypertensive Agents
Cardiovascular Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on July 30, 2015