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

• ClinicalTrials.gov Identifier: NCT01311362
• Recruitment Status: Completed
• First Posted: March 9, 2011
• Results First Posted: June 2, 2015
• Last Update Posted: May 31, 2017
• Sponsor: Gerd Mikus
• Information provided by (Responsible Party): Gerd Mikus, Heidelberg University

Study Description

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.

Condition or disease	Intervention/treatment
Drug Interactions	Drug: St. Johns wort

Study Design

• Study Type: Observational
• Actual Enrollment: 20 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Influence of CYP3A4-induction by St. John's Wort (SJW) on the Steady State Pharmacokinetics of Ambrisentan
• Study Start Date: March 2011
• Actual Primary Completion Date: April 2012
• Actual Study Completion Date: December 2012

Groups and Cohorts

Group/Cohort	Intervention/treatment
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	Drug: 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; Other Name: Jarsin
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	Drug: 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; Other Name: Jarsin

Outcome Measures

Primary Outcome Measures :

1. AUC of Ambrisentan [ Time Frame: after first dose, at steady-state, during St John's wort ]
2. Cmax of Ambrisentan [ Time Frame: after first dose, at steady-state and during St John's wort ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

healthy subjects

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

Contacts and Locations

Locations

Germany

University Hospital Heidelberg

Heidelberg, Germany, 69120

Sponsors and Collaborators

Gerd Mikus

Investigators

• Principal Investigator: Gerd Mikus, Prof. Dr.; deputy head of department

More Information

Publications:

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.

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.

• Responsible Party: Gerd Mikus, Head of Clinical Research Unit, Heidelberg University
• ClinicalTrials.gov Identifier: NCT01311362
• Other Study ID Numbers: K331; 2010-022868-13 ( EudraCT Number )
• First Posted: March 9, 2011
• Results First Posted: June 2, 2015
• Last Update Posted: May 31, 2017
• Last Verified: May 2017

Keywords provided by Gerd Mikus, Heidelberg University:

Steady-state; Ambrisentan; St. Johns Wort