Clinical trial NCT01258504: Influence of CYP3A4-induction by St. John's Wort on the Steady State Pharmacokinetics of Bosentan
Official title: Influence of Cytochrome P450 3A4 (CYP3A4)-Induction by St. John's Wort (SJW) on the Steady State Pharmacokinetics of Bosentan
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Drug Interactions
Keywords: Steady-state
Bosentan
St. Johns Wort
Lead sponsor: Heidelberg University
Sponsor class: OTHER
First posted: 2010-12-13
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: healthy subjects

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.

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

Primary outcomes:
measure: AUC of Bosentan
timeFrame: 0-infinity; during dosing interval
measure: Cmax of Bosentan
timeFrame: after first dose, at steady-state and during SJW
Secondary outcomes:
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg
Study officials:
affiliation: deputy head of department
name: Gerd Mikus, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.