Drug Interactions
Conditions
Keywords
Steady-state, Bosentan, St. Johns Wort
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.
Interventions
DRUGSt. 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
Sponsors
Gerd Mikus
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| AUC of Bosentan | 0-infinity; during dosing interval |
| Cmax of Bosentan | after first dose, at steady-state and during SJW |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bosentan 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 | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Bosentan |
|---|---|
| Age, Continuous | 35 years STANDARD_DEVIATION 11 |
| Region of Enrollment Germany | 13 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 13 | 9 / 13 | 4 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 | 0 / 13 |
Outcome results
Primary
AUC of Bosentan
Time frame: 0-infinity; during dosing interval
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Bosentan After First Dose | AUC of Bosentan | 9540 h*ng/ml |
| Bosentan at Steady-state | AUC of Bosentan | 5710 h*ng/ml |
| Bosentan During St John's Wort | AUC of Bosentan | 5020 h*ng/ml |
Primary
Cmax of Bosentan
Time frame: after first dose, at steady-state and during SJW
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Bosentan After First Dose | Cmax of Bosentan | 1620 ng/ml |
| Bosentan at Steady-state | Cmax of Bosentan | 1370 ng/ml |
| Bosentan During St John's Wort | Cmax of Bosentan | 1280 ng/ml |