Drug Interaction Study
Conditions
Brief summary
Single-center, open-label, sequential treatment study to investigate the influence of the combined P-glycoprotein and CYP3A4 inducer hypericum perforatum on the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy volunteers.
Detailed description
Each session (one with and one without preceding CYP induction) will start with phenotyping using 25 mg fexofenadine orally for P-gp phenotyping and 2 mg midazolam orally for cytochrome P450 (CYP) 3A4 phenotyping. After a washout period of 5 days, subjects will receive a single oral dose of 20 mg rivaroxaban, a dose currently approved for human use in clinical routine. The same procedure will be repeated after pretreatment with St. John's wort extract (Jarsin®) twice daily 450 mg po (dose usually used in clinical routine) for 2 weeks.
Interventions
DRUGSt Johns Wort Extract
20 mg rivaroxaban after supplementation with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks.
DRUGRivaroxaban
20 mg rivaroxaban.
Sponsors
Bayer
Insel Gruppe AG, University Hospital Bern
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Men or women, age between 18 and 45 years (inclusive) at screening * BMI between 18 and 28 kg/m2 (inclusive) at screening * No clinically significant findings on the physical examination at screening * Hematology and clinical chemistry results not deviating from the normal range to a clinically relevant extent at screening * Ability to communicate well with the investigator and to understand and comply with the requirements of the study * Women of child-bearing age: willingness of using a double barrier contraception method during the study, i.e. a hormonal method (oral contraceptive, intrauterine device) in combination with a mechanical barrier (e.g. condom, diaphragm) * Signed informed consent
Exclusion criteria
* Known allergic reaction to any excipient of the drug formulations * Known photosensitivity * Smoking * History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening * Loss of ≥ 250 ml of blood within 3 months prior to screening, including blood donation * Treatment with an investigational drug within 30 days prior to screening * Previous treatment with any prescribed or over-the-counter medications (including herbal medicines such as St. John's wort) within 2 weeks prior to screening * Pregnant (positive results from urine drug screen at screening) or lactating women * History or clinical evidence of any disease (e.g. gastrointestinal tract disease) and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs, or which might increase the risk for toxicity * Legal incapacity or limited legal capacity at screening * Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic outcome measures: area under the curve (AUC). | AUC will be calculated from the concentration-time plot (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions) | Effect of pretreatment with hypericum perforatum on geometric mean AUC. |
| Pharmacokinetic outcome measures: maximal concentration of rivaroxaban. | Will be obtained from the individual plasma concentration data (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions) | Effect of pretreatment with hypericum perforatum on maximal concentration of rivaroxaban. |
| Pharmacodynamic outcome measures: Factor Xa activity | Time points used for analysis: pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions | Displayed as maximal effect (Emax) and parametrized by calculating the area under the time-effect curves (AUEC)). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phenotyping metrics: AUC ratios midazolam | Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration | AUC ratios of midazolam and 1'-hydroxymidazolam |
| Pharmacokinetic parameters: Time to reach maximal concentration | Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions | Time to reach maximal concentration of rivaroxaban |
| Phenotyping metrics: Single point metabolic ratios midazolam | Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration | Single point metabolic ratios of midazolam and 1'-hydroxymidazolam |
| Pharmacokinetic parameters: Plasma elimination half-life | Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions | Plasma elimination half-life of rivaroxaban |
| Phenotyping metrics: AUC fexofenadine | Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration | Estimated AUC of fexofenadine |
Countries
Switzerland
Outcome results
None listed