Influence of OATP1B1 and CYP2C9 Genotypes on the Pharmacokinetics of Steady State Bosentan Before and During CYP3A4-inhibition by Clarithromycin
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- AUC
研究概览
简要总结
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).
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Bosentan
Haplotypes of CYP2C9 and OATP1B1 characterisation of CYP2C9 (CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910)) and OATP1B1 (SLCO1B1*15 (rs2306283, rs4149056))
干预措施: Bosentan (Drug)
结局指标
主要结局
AUC
时间窗: 0-infinity; dosing interval
AUC of bosentan after first-dose, at steady-state and during clarithromycin therapy
Cmax
时间窗: after first dose, at steady-state, during clarithromycin
Cmax after the first dose of bosentan, at steady-state, during clarithromycin
次要结局
未报告次要终点
研究者
Gerd Mikus
Prof. Dr. med. Gerd Mikus
Heidelberg University