Rivaroxaban Hypericum Trial

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

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.

Study Overview

• Status: Completed
• Conditions: Drug Interaction Study
• Intervention / Treatment: Drug: Rivaroxaban; Drug: St Johns Wort Extract

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 Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Bern, Switzerland
    • Inselspital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: Rivaroxaban; Single oral dose of 20 mg rivaroxaban	Drug: Rivaroxaban; 20 mg rivaroxaban.
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: Rivaroxaban; 20 mg rivaroxaban.; 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: Inducer of CYP3A4 and P-gp

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Collaborators: Bayer
• Investigators: Study Director: Inselpital, Sponsor: Inselspital, Bern University Hospital

Publications and helpful links

General Publications

• Scholz I, Liakoni E, Hammann F, Grafinger KE, Duthaler U, Nagler M, Krahenbuhl S, Haschke M. Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans. Br J Clin Pharmacol. 2021 Mar;87(3):1466-1474. doi: 10.1111/bcp.14553. Epub 2020 Oct 25.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 13, 2019
• Primary Completion (ACTUAL): April 9, 2019
• Study Completion (ACTUAL): April 9, 2019

Study Registration Dates

• First Submitted: January 4, 2019
• First Submitted That Met QC Criteria: January 4, 2019
• First Posted (ACTUAL): January 8, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 3, 2020
• Last Update Submitted That Met QC Criteria: October 30, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: Studien-Nr. 3459

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No