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

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

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.

Study Overview

• Status: Completed
• Conditions: Drug Interactions
• Intervention / Treatment: Drug: St. Johns wort

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• Germany
  • Heidelberg, Germany, 69120
    • University Hospital Heidelberg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

healthy subjects

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

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 Names: 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 Names: Jarsin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Gerd Mikus

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (ACTUAL): April 1, 2012
• Study Completion (ACTUAL): December 1, 2012

Study Registration Dates

• First Submitted: March 8, 2011
• First Submitted That Met QC Criteria: March 8, 2011
• First Posted (ESTIMATE): March 9, 2011

Study Record Updates

• Last Update Posted (ACTUAL): May 31, 2017
• Last Update Submitted That Met QC Criteria: May 3, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Steady-state; St. Johns Wort; Ambrisentan
• Other Study ID Numbers: K331; 2010-022868-13 (EUDRACT_NUMBER)