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

NCT ID: NCT01311362

Last Updated: 2017-05-31

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 20 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2011-03-31
• Study Completion Date: 2012-12-31

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.

Conditions

Drug Interactions

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

CYP2C19 wild type

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

St. Johns wort

Intervention Type: DRUG

• 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

CYP2C19 mutant

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

St. Johns wort

Intervention Type: DRUG

• 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

Interventions

St. 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

Intervention Type: DRUG

Other Intervention Names

Jarsin

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Gerd Mikus

OTHER

Sponsor Role: lead

Responsible Party

Gerd Mikus

Head of Clinical Research Unit

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Gerd Mikus, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

deputy head of department

Locations

University Hospital Heidelberg

Heidelberg, , Germany

Countries

Germany

References

Spence R, Mandagere A, Richards DB, Magee MH, Dufton C, Boinpally R. Potential for pharmacokinetic interactions between ambrisentan and cyclosporine. Clin Pharmacol Ther. 2010 Oct;88(4):513-20. doi: 10.1038/clpt.2010.120. Epub 2010 Sep 1.

Reference Type: BACKGROUND

PMID: 20811346 (View on PubMed)

Harrison B, Magee MH, Mandagere A, Walker G, Dufton C, Henderson LS, Boinpally R. Effects of rifampicin (rifampin) on the pharmacokinetics and safety of ambrisentan in healthy subjects: a single-sequence, open-label study. Clin Drug Investig. 2010;30(12):875-885. doi: 10.2165/11539110-000000000-00000.

Reference Type: BACKGROUND

PMID: 20923245 (View on PubMed)

Other Identifiers

2010-022868-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

K331

Identifier Type: -

Identifier Source: org_study_id