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

• Sponsor: Gerd Mikus (Other)
• Overall Status: Completed
• CT.gov ID: NCT01311362
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Duration (Months): 21.1
• Patients Per Site Per Month: 0.9

Study Details

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	Phase
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: Mar 1, 2011
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	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

Outcome Measures

Primary Outcome Measures

1. AUC of Ambrisentan [after first dose, at steady-state, during St John's wort]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

	Site	City	State	Country	Postal Code
1	University Hospital Heidelberg	Heidelberg		Germany	69120

Sponsors and Collaborators

• Gerd Mikus

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.

• Responsible Party: Gerd Mikus, Head of Clinical Research Unit, Heidelberg University
• ClinicalTrials.gov Identifier: NCT01311362
• Other Study ID Numbers: K331; 2010-022868-13
• First Posted: Mar 9, 2011
• Last Update Posted: May 31, 2017
• Last Verified: May 1, 2017

• Keywords provided by Gerd Mikus, Head of Clinical Research Unit, Heidelberg University: Steady-state; Ambrisentan; St. Johns Wort

Study Results

Participant Flow

Arm/Group Title	Ambrisentan After First Dose
Arm/Group Description	administration of ambrisentan 5 mg p.o. single dose administration of ambrisentan 5 mg p.o. q.d. on day 3-10 administration of ambrisentan 5 mg p.o. q.d on day 11-20 and administration of SJW 300 mg p.o. t.i.d. on day 11-20
Period Title: Ambrisentan Single Dose
STARTED	20
COMPLETED	20
NOT COMPLETED	0
Period Title: Ambrisentan Single Dose
STARTED	20
COMPLETED	20
NOT COMPLETED	0
Period Title: Ambrisentan Single Dose
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Ambrisentan
Arm/Group Description	administration of ambrisentan 5 mg p.o. single dose administration of ambrisentan 5 mg p.o. q.d. on day 3-10 administration of ambrisentan 5 mg p.o. q.d on day 11-20 and administration of SJW 300 mg p.o. t.i.d. on day 11-20
Overall Participants	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.3 (7.7)
Sex: Female, Male (Count of Participants)
Female	4 20%
Male	16 80%
Region of Enrollment (participants) [Number]
Germany	20 100%

Outcome Measures

1. Primary Outcome

Title	AUC of Ambrisentan
Time Frame	after first dose, at steady-state, during St John's wort

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ambrisentan After First Dose	Ambrisentan at Steady-state	Ambrisentan During St John's Wort
Arm/Group Description	administration of ambrisentan 5 mg p.o. single dose	administration of ambrisentan 5 mg p.o. q.d. on day 3-10	administration of ambrisentan 5 mg p.o. q.d. on day 11-20 and administration of SJW 300 mg t.i.d. on day 11-20
Measure Participants	20	20	20
Geometric Mean (95% Confidence Interval) [h*ng/ml]	3670	3520	2790

2. Primary Outcome

Title	Cmax of Ambrisentan
Time Frame	after first dose, at steady-state and during St John's wort

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ambrisentan After First Dose	Ambrisentan at Steady-state	Ambrisentan During St John's Wort
Arm/Group Description	administration of ambrisentan 5 mg p.o. single dose	administration of ambrisentan 5 mg p.o. q.d. on day 3-10	administration of ambrisentan 5 mg p.o. q.d. on day 11-20 and administration of SJW 300 mg p.o. t.i.d. on day 11-20
Measure Participants	20	20	20
Geometric Mean (95% Confidence Interval) [ng/ml]	447	456	383

Adverse Events

Arm/Group Title	Ambrisentan After First Dose		Ambrisentan at Steady-state		Ambrisentan During St John's Wort
Arm/Group Description	administration of ambrisentan 5 mg p.o. single dose		administration of ambrisentan 5 mg p.o. q.d. on day 3-10		administration of ambrisentan 5 mg p.o. q.d. on day 11-20 and administration of SJW 300 mg p.o. t.i.d. on day 11-20
All Cause Mortality
	Ambrisentan After First Dose		Ambrisentan at Steady-state		Ambrisentan During St John's Wort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ambrisentan After First Dose		Ambrisentan at Steady-state		Ambrisentan During St John's Wort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Ambrisentan After First Dose		Ambrisentan at Steady-state		Ambrisentan During St John's Wort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/20 (70%)		14/20 (70%)		6/20 (30%)
General disorders
Headache	9/20 (45%)		9/20 (45%)		4/20 (20%)
nasal congestion	5/20 (25%)		5/20 (25%)		2/20 (10%)
Back pain	1/20 (5%)		1/20 (5%)		0/20 (0%)
Nasopharyngitis	1/20 (5%)		1/20 (5%)		2/20 (10%)
heart palpitation	1/20 (5%)		1/20 (5%)		0/20 (0%)
heat sensation	1/20 (5%)		1/20 (5%)		0/20 (0%)
thoracic discomfort	1/20 (5%)		1/20 (5%)		0/20 (0%)
flush	1/20 (5%)		1/20 (5%)		0/20 (0%)
pressure sensation in head	1/20 (5%)		1/20 (5%)		1/20 (5%)
diarrhoea	1/20 (5%)		1/20 (5%)		0/20 (0%)
nightmares	1/20 (5%)		1/20 (5%)		0/20 (0%)
Hepatobiliary disorders
increase of liver transaminases	3/20 (15%)		3/20 (15%)		0/20 (0%)

Limitations/Caveats

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

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.