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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01425229
First Posted: August 29, 2011
Last Update Posted: May 31, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Gerd Mikus, Heidelberg University
  Purpose

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).


Condition Intervention
Drug Interactions Drug: Bosentan

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Influence of OATP1B1 and CYP2C9 Genotypes on the Pharmacokinetics of Steady State Bosentan Before and During CYP3A4-inhibition by Clarithromycin

Resource links provided by NLM:


Further study details as provided by Gerd Mikus, Heidelberg University:

Primary Outcome Measures:
  • AUC [ Time Frame: 0-infinity; dosing interval ]
    AUC of bosentan after first-dose, at steady-state and during clarithromycin therapy

  • Cmax [ Time Frame: after first dose, at steady-state, during clarithromycin ]
    Cmax after the first dose of bosentan, at steady-state, during clarithromycin


Enrollment: 16
Study Start Date: June 2011
Study Completion Date: December 2012
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Bosentan
Haplotypes of CYP2C9 and OATP1B1 characterisation of CYP2C9 (CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910)) and OATP1B1 (SLCO1B1*15 (rs2306283, rs4149056))
Drug: Bosentan
  • 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
Other Name: Tracleer

  Eligibility

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
healthy subjects
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 × 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.

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01425229


Locations
Germany
University Hospital Heidelberg
Heidelberg, Germany
Sponsors and Collaborators
Gerd Mikus
Investigators
Principal Investigator: Gerd Mikus, Prof. Dr. deputy head of department
  More Information

Publications:
Responsible Party: Gerd Mikus, Prof. Dr. med. Gerd Mikus, Heidelberg University
ClinicalTrials.gov Identifier: NCT01425229     History of Changes
Other Study ID Numbers: K318
2010-021392-93 ( EudraCT Number )
First Submitted: August 26, 2011
First Posted: August 29, 2011
Results First Submitted: July 8, 2014
Results First Posted: August 4, 2015
Last Update Posted: May 31, 2017
Last Verified: May 2017

Keywords provided by Gerd Mikus, Heidelberg University:
steady state
bosentan
clarithromycin

Additional relevant MeSH terms:
Clarithromycin
Bosentan
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antihypertensive Agents
Endothelin Receptor Antagonists