Drug Interactions
Conditions
Keywords
steady state, bosentan, clarithromycin
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).
Interventions
DRUGBosentan
* 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
Sponsors
Gerd Mikus
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bosentan Bosentan PK | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Bosentan |
|---|---|
| Age, Continuous | 31.6 years STANDARD_DEVIATION 7.8 |
| Region of Enrollment Germany | 16 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 16 | 9 / 16 | 9 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
AUC
AUC of bosentan after first-dose, at steady-state and during clarithromycin therapy
Time frame: 0-infinity; dosing interval
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Bosentan After First Dose | AUC | 11900 h*ng/ml |
| Bosentan at Steady-state | AUC | 6830 h*ng/ml |
| Bosentan During Clarithromycin | AUC | 25500 h*ng/ml |
Primary
Cmax
Cmax after the first dose of bosentan, at steady-state, during clarithromycin
Time frame: after first dose, at steady-state, during clarithromycin
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Bosentan After First Dose | Cmax | 1890 ng/ml |
| Bosentan at Steady-state | Cmax | 1460 ng/ml |
| Bosentan During Clarithromycin | Cmax | 5570 ng/ml |