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

Completed

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
CYP2C19 wild type	St. Johns wort	CYP2C19 wild type ="extensive metaboliser" * Administration of ambrisentan: 5 mg p.o. q.d. on day 1 and days 3-20 * Administration of St. Johns wort: 300 mg p.o. three times a day (t.i.d.) on days 11-20
CYP2C19 mutant	St. Johns wort	CYP2C19 \2/\2 or \2/\3 or \3/\3 = "poor metaboliser" * Administration of ambrisentan: 5 mg p.o. q.d. on day 1 and days 3-20 * Administration of St. Johns wort: 300 mg p.o. three times a day (t.i.d.) on days 11-20

Primary Outcome Measures

Name	Time	Method
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

Secondary Outcome Measures