Rivaroxaban Hypericum Trial

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Hypericum Perforatum (St. John's Wort) on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Humans

Conditions
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Drug Interaction Study

Intervention / Treatment
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* Drug: St Johns Wort Extract
* Drug: Rivaroxaban


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Rivaroxaban<br>Single oral dose of 20 mg rivaroxaban | Drug: Rivaroxaban<br>* 20 mg rivaroxaban.<br>|
| Other: Rivaroxaban after CYP- and P-gp induction<br>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<br>* 20 mg rivaroxaban after supplementation with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks.<br>* Other names: Inducer of CYP3A4 and P-gp;Drug: Rivaroxaban<br>* 20 mg rivaroxaban.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic outcome measures: area under the curve (AUC). | Effect of pretreatment with hypericum perforatum on geometric mean 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) | 
| Pharmacokinetic outcome measures: maximal concentration of rivaroxaban. | Effect of pretreatment with hypericum perforatum on 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) | 
| Pharmacodynamic outcome measures: Factor Xa activity | Displayed as maximal effect (Emax) and parametrized by calculating the area under the time-effect curves (AUEC)). | Time points used for analysis: pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameters: Time to reach maximal concentration | Time to reach maximal concentration of rivaroxaban | Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions | 
| Pharmacokinetic parameters: Plasma elimination half-life | Plasma elimination half-life of rivaroxaban | Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions | 
| Phenotyping metrics: AUC fexofenadine | Estimated AUC of fexofenadine | Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration | 
| Phenotyping metrics: AUC ratios midazolam | AUC ratios of midazolam and 1'-hydroxymidazolam | Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration | 
| Phenotyping metrics: Single point metabolic ratios midazolam | Single point metabolic ratios of midazolam and 1'-hydroxymidazolam | Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration |