Drug Interactions
Conditions
Keywords
Steady-state, Ambrisentan, St. Johns Wort
Brief summary
The aim of the present study is to assess the impact of CYP3A4-induction by SJW on steady state ambrisentan and the impact of the cytochrome P450 2C19 (CYP2C19) genotype (\*2 and \*3 allele vs. wild type; \ 2-5% poor metabolisers in Caucasian population) on the pharmacokinetics of ambrisentan in healthy volunteers.
Interventions
DRUGSt. Johns wort
* Administration of ambrisentan: 5 mg p.o. q.d. on day 1 and days 3-20 * Administration of SJW: 300 mg p.o. three times a day (t.i.d.) on days 11-20
Sponsors
Gerd Mikus
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 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 CYP2C19 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 * Contraindication against midazolam, ambrisentan, or SJW or any known intolerance to any of these substances or their additives
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| AUC of Ambrisentan | after first dose, at steady-state, during St John's wort |
| Cmax of Ambrisentan | after first dose, at steady-state and during St John's wort |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ambrisentan administration of ambrisentan 5 mg p.o. single dose administration of ambrisentan 5 mg p.o. q.d. on day 3-10 administration of ambrisentan 5 mg p.o. q.d on day 11-20 and administration of SJW 300 mg p.o. t.i.d. on day 11-20 | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Ambrisentan |
|---|---|
| Age, Continuous | 31.3 years STANDARD_DEVIATION 7.7 |
| Region of Enrollment Germany | 20 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 16 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 | 14 / 20 | 14 / 20 | 6 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
AUC of Ambrisentan
Time frame: after first dose, at steady-state, during St John's wort
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ambrisentan After First Dose | AUC of Ambrisentan | 3670 h*ng/ml |
| Ambrisentan at Steady-state | AUC of Ambrisentan | 3520 h*ng/ml |
| Ambrisentan During St John's Wort | AUC of Ambrisentan | 2790 h*ng/ml |
Primary
Cmax of Ambrisentan
Time frame: after first dose, at steady-state and during St John's wort
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ambrisentan After First Dose | Cmax of Ambrisentan | 447 ng/ml |
| Ambrisentan at Steady-state | Cmax of Ambrisentan | 456 ng/ml |
| Ambrisentan During St John's Wort | Cmax of Ambrisentan | 383 ng/ml |