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

NCT01311362 | Completed Results

• 2 other identifiers: K3312010-022868-13
• Study Type: observational
• Target: 20
• Locations: 1 country
• Sites: 1

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

Keywords

Steady-state; Ambrisentan; St. Johns Wort

Outcome Measures

Primary Outcomes (2)

• 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

Study Arms (2)

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

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

Interventions

St. Johns wort 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

Also known as: Jarsin

CYP2C19 mutant; CYP2C19 wild type

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

healthy subjects

You may qualify if:

• 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.

You may not qualify if:

• 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 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

Sponsors & Collaborators

• Gerd Mikus: lead

Study Sites (1)

University Hospital Heidelberg

Heidelberg, 69120, Germany

Location

Related Publications (2)

• 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.

  PMID: 20811346 BACKGROUND

• 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.

  PMID: 20923245 BACKGROUND

MeSH Terms

Interventions

Hypericum extract LI 160

Limitations and Caveats

The extent of this interaction was small and thus likely without clinical relevance.

Results Point of Contact

• Title: Prof. Dr. med. Gerd Mikus
• Organization: University of Heidelberg

gerd.mikus@med.uni-heidelberg.de

4966215639197

Study Officials

• Gerd Mikus, Prof. Dr.

  deputy head of department

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of Clinical Research Unit

Study Record Dates

• First Submitted: March 8, 2011
• First Posted: March 9, 2011
• Study Start: March 1, 2011
• Primary Completion: April 1, 2012
• Study Completion: December 1, 2012
• Last Updated: May 31, 2017
• Results First Posted: June 2, 2015

Record last verified: 2017-05

Locations

DE (1)