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

Study Overview
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Brief Summary
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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.

Official Title
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Influence of CYP3A4-induction by St. John's Wort (SJW) on the Steady State Pharmacokinetics of Ambrisentan

Conditions
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Drug Interactions

Intervention / Treatment
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* Drug: St. Johns wort


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CYP2C19 wild type<br>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 | Drug: St. Johns wort<br>* 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<br>* Other names: Jarsin;|
| CYP2C19 mutant<br>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 | Drug: St. Johns wort<br>* 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<br>* Other names: Jarsin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Steady-state, Ambrisentan, St. Johns Wort