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

Gerd Mikus

Status: Completed

Conditions: Drug Interactions

Treatments: Drug: St. Johns wort

Study type: Observational

Funder types: Other

Identifiers

NCT01311362

2010-022868-13 (EudraCT Number)

K331

Details and patient eligibility

About

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.

Enrollment: 20 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

20 participants in 2 patient groups

CYP2C19 wild type

Description:

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

Treatment:

Drug: St. Johns wort

CYP2C19 mutant

Description:

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

Treatment:

Drug: St. Johns wort