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

Influence of OATP1B1 and CYP2C9 Genotypes on the Pharmacokinetics of Steady State Bosentan Before and During CYP3A4-inhibition by Clarithromycin

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).

Study Overview

• Status: Completed
• Conditions: Drug Interactions
• Intervention / Treatment: Drug: Bosentan

• Study Type: Observational
• Enrollment (Actual): 16

Contacts and Locations

Study Locations

• Germany
  • Heidelberg, Germany
    • University Hospital Heidelberg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

healthy subjects

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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 Names: Tracleer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Gerd Mikus

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: August 26, 2011
• First Submitted That Met QC Criteria: August 26, 2011
• First Posted (Estimate): August 29, 2011

Study Record Updates

• Last Update Posted (Actual): May 31, 2017
• Last Update Submitted That Met QC Criteria: May 3, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: steady state; clarithromycin; bosentan
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: K318; 2010-021392-93 (EudraCT Number)