Clinical trial NCT03796377: Rivaroxaban Hypericum Trial
Official title: Effects of Hypericum Perforatum (St. John's Wort) on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Drug Interaction Study
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2019-01-08
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Pharmacokinetic outcome measures: area under the curve (AUC).
timeFrame: 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)
measure: Pharmacokinetic outcome measures: maximal concentration of rivaroxaban.
timeFrame: 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)
measure: Pharmacodynamic outcome measures: Factor Xa activity
timeFrame: 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 outcomes:
measure: Pharmacokinetic parameters: Time to reach maximal concentration
timeFrame: Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
measure: Pharmacokinetic parameters: Plasma elimination half-life
timeFrame: Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
measure: Phenotyping metrics: AUC fexofenadine
timeFrame: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
measure: Phenotyping metrics: AUC ratios midazolam
timeFrame: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
measure: Phenotyping metrics: Single point metabolic ratios midazolam
timeFrame: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: Inselspital
Study officials:
affiliation: Sponsor: Inselspital, Bern University Hospital
name: Inselpital
role: STUDY_DIRECTOR
References:
citation: 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.