Influence of OATP1B1 and CYP2C9 Genotypes on the Pharmacokinetics of Bosentan Before and During Clarithromycin

NCT01425229 | Completed Results

• 2 other identifiers: K3182010-021392-93
• Study Type: observational
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of the present study is to assess the impact of the OATP1B1 genotype (SLCO1B1\*15 vs. wild type; \~2% SLCO1B1\*15 haplotypes in Caucasian population) and the CYP2C9 genotype (\*2 and \*3 allele vs. wild type; \~5% poor metabolisers in Caucasian population) on the pharmacokinetics of bosentan and the impact of CYP3A4-inhibition by clarithromycin on steady state bosentan which is a CYP3A4 inducer itself. This study will focus on differential effects of genotypes and co-medication on the pharmacokinetics of bosentan at the metabolic and transport level. Participants will be genotyped for CYP2C9 (inclusion criterion), OATP1B1 (inclusion criterion), and CYP3A5 (no inclusion criterion).

Conditions

Drug Interactions

Keywords

steady state; bosentan; clarithromycin

Outcome Measures

Primary Outcomes (2)

• AUC

  AUC of bosentan after first-dose, at steady-state and during clarithromycin therapy

  0-infinity; dosing interval

• Cmax

  Cmax after the first dose of bosentan, at steady-state, during clarithromycin

  after first dose, at steady-state, during clarithromycin

Study Arms (1)

Bosentan

Haplotypes of CYP2C9 and OATP1B1 characterisation of CYP2C9 (CYP2C9\*2 (rs1799853), CYP2C9\*3 (rs1057910)) and OATP1B1 (SLCO1B1\*15 (rs2306283, rs4149056))

Drug: Bosentan

Interventions

Bosentan DRUG

* Administration of bosentan: 1 x 125 mg p.o. on day 1, 2 x 125 mg p.o. on day 2-14 * Administration of clarithromycin: 2 x 500 mg p.o. on day 11-14

Also known as: Tracleer

Bosentan

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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 × 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 CYP2C9 and OATP1B1 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

Sponsors & Collaborators

• Gerd Mikus: lead

Study Sites (1)

University Hospital Heidelberg

Heidelberg, Germany

Location

Related Publications (1)

• Dingemanse J, van Giersbergen PL. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089-115. doi: 10.2165/00003088-200443150-00003.

  PMID: 15568889 BACKGROUND

MeSH Terms

Interventions

Bosentan

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

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

gerd.mikus@med.uni-heidelberg.de

4962215639197

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: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. med. Gerd Mikus

Study Record Dates

• First Submitted: August 26, 2011
• First Posted: August 29, 2011
• Study Start: June 1, 2011
• Primary Completion: May 1, 2012
• Study Completion: December 1, 2012
• Last Updated: May 31, 2017
• Results First Posted: August 4, 2015

Record last verified: 2017-05

Locations

DE (1)