Rivaroxaban Hypericum Trial
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Other: Rivaroxaban Single oral dose of 20 mg rivaroxaban |
Drug: Rivaroxaban
20 mg rivaroxaban.
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Other: Rivaroxaban after CYP- and P-gp induction Single oral dose of 20 mg rivaroxaban after pretreatment with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks. |
Drug: St Johns Wort Extract
20 mg rivaroxaban after supplementation with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks.
Other Names:
Drug: Rivaroxaban
20 mg rivaroxaban.
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Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
- 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
- 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
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
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Men or women, age between 18 and 45 years (inclusive) at screening
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BMI between 18 and 28 kg/m2 (inclusive) at screening
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No clinically significant findings on the physical examination at screening
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Hematology and clinical chemistry results not deviating from the normal range to a clinically relevant extent at screening
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Ability to communicate well with the investigator and to understand and comply with the requirements of the study
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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)
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Signed informed consent
Exclusion Criteria:
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Known allergic reaction to any excipient of the drug formulations
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Known photosensitivity
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Smoking
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History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening
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Loss of ≥ 250 ml of blood within 3 months prior to screening, including blood donation
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Treatment with an investigational drug within 30 days prior to screening
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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
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Pregnant (positive results from urine drug screen at screening) or lactating women
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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
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Legal incapacity or limited legal capacity at screening
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Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Inselspital | Bern | Switzerland |
Sponsors and Collaborators
- University Hospital Inselspital, Berne
- Bayer
Investigators
- Study Director: Inselpital, Sponsor: Inselspital, Bern University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Studien-Nr. 3459