Clinical trial NCT01311362: Influence of Cytochrome CYP3A4-induction by St. John's Wort on the Steady State Pharmacokinetics of Ambrisentan
Official title: Influence of CYP3A4-induction by St. John's Wort (SJW) on the Steady State Pharmacokinetics of Ambrisentan
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Drug Interactions
Keywords: Steady-state
Ambrisentan
St. Johns Wort
Lead sponsor: Heidelberg University
Sponsor class: OTHER
First posted: 2011-03-09
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: healthy subjects

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.


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

Primary outcomes:
measure: AUC of Ambrisentan
timeFrame: after first dose, at steady-state, during St John's wort
measure: Cmax of Ambrisentan
timeFrame: after first dose, at steady-state and during St John's wort
Secondary outcomes:
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg
Study officials:
affiliation: deputy head of department
name: Gerd Mikus, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.