Rivaroxaban Hypericum Trial

Drug Interaction Study Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03796377
• Other study ID #: Studien-Nr. 3459
• Status: Completed
• Phase: Phase 1
• Start date: February 13, 2019
• Est. completion date: April 9, 2019

Study information

• Verified date: October 2020
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: April 9, 2019
• Est. primary completion date: April 9, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Drug Interaction Study

Intervention

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.
• Rivaroxaban
20 mg rivaroxaban.

Locations

Country	Name	City	State
Switzerland	Inselspital	Bern

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne	Bayer

Country where clinical trial is conducted

Switzerland, 

References & Publications (1)

Scholz I, Liakoni E, Hammann F, Grafinger KE, Duthaler U, Nagler M, Krähenbühl S, Haschke M. Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans. Br J Clin Pharmacol. 2020 Sep 22. doi: 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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	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
Secondary	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
Secondary	Phenotyping metrics: AUC fexofenadine	Estimated AUC of fexofenadine	Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
Secondary	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
Secondary	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