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

Completed

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).

Recruitment & Eligibility

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

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
AUC	0-infinity; dosing interval	AUC of bosentan after first-dose, at steady-state and during clarithromycin therapy
Cmax	after first dose, at steady-state, during clarithromycin	Cmax after the first dose of bosentan, at steady-state, during clarithromycin

Secondary Outcome Measures