Drug-gene-nutraceutical Interactions of Cannabidiol and Tacrolimus

April 5, 2024 updated by: Michael Eadon, Indiana University
The information learned in these studies will help to inform doctors as to how to appropriately adjust doses of cannabidiol and tacrolimus in order to improve health outcomes and long-term treatment success for transplant recipients.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The commercial availability of cannabidiol, or CBD oil, has increased in the United Stated and this supplement has the potential to cause a variety of drug-drug interactions, including in solid organ transplant recipients who receive tacrolimus to prevent rejection. Through a series of pharmacokinetic and pharmacodynamics assays, this proposal will identify gene-drug and drug-drug interactions (DDI), including those that place transplant recipients at risk for increased toxicity related to their immunosuppression. The information learned in these studies will help to inform practitioners as to whether cannabidiol needs to be avoided in transplant recipients and how to appropriately adjust doses of CBD and immunosuppression in order to improve health outcomes and long-term treatment success in this high-risk population.

Study Type

Interventional

Enrollment (Estimated)

72

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Recruiting
        • IU Health University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Age 18-65
  • Are judged healthy enough to participate as determined by and decided from a pre-enrollment screening session that includes medical history and laboratory tests such as blood and urine tests, and electrocardiography (EKG).
  • Agree to refrain from taking any prescription medications, over-the-counter medications, and herbal, dietary, and alternative supplements that may interact with the metabolism of the study drugs at least 2 weeks prior to the start of the study and until study completion.
  • Are willing to commit the time requested for this study
  • Are willing to refrain from smoking or use of tobacco or marijuana for at least two weeks prior to and until the completion of the study (the entire study lasts for approximately 26 days).

Additional Criteria for the Healthy volunteer study:

• Have a GFR above 60 ml/min/1.73m2 with proteinuria less than 0.3 grams by urine protein to creatinine ratio or 24 hour urine collection

Additional Criteria for the CKD study:

  • Have either:
  • A GFR between 16 ml/min and 60 ml/min/1.73m2 or
  • The presence of greater than 0.3 grams of proteinuria by urine protein to creatinine ratio or 24 hour urine collection, but less than 3.5 gm of nephrotic range proteinuria as hypoalbuminemia may impact protein binding.

Exclusion Criteria:

  • Unable to provide informed consent
  • Have history of intolerance, allergic reactions (e.g. rash) or other forms of hypersensitivities to any of the study medications (tacrolimus or cannabidiol);
  • Are currently taking sedative agents, including agents for insomnia
  • Are underweight (body mass index (BMI) less than 18.5) or overweight [body mass index (BMI) greater than 35]
  • Have a positive pregnancy serum or urine test obtained just prior to each study, or are breast feeding
  • Are night shift workers
  • Have an eGFR < 15 ml/min/1.73m2 or are on dialysis.
  • Have compromised liver function as defined by pre-screening bilirubin, AST and ALT testing including any elevation of bilirubin or AST/ALT more than 2x the upper limit of normal.
  • Have a positive urine drug screen for Cannabis or Marijuana at screening.
  • Have a Hgb < 10.0 g/dL
  • Have gastrointestinal (digestive) disorders such as persistent diarrhea or malabsorption that would interfere with the absorption of orally administered drugs
  • Have a history of or current seizure disorder
  • Are currently on immunosuppression or are immunosuppressed.
  • Are recipients of a current allograft (heart, kidney, pancreas, liver, intestine, lung, stem cell transplant).
  • Have baseline EKG readings that are abnormal that could place the patient at the high risk.
  • Have alcohol (more than 4 alcoholic drinks per day on a regular basis) or drug abuse, including opioids, or have used tobacco products or marijuana within the past three months, and are unwilling or unable to stop taking these medications two weeks prior to and during the entire study period
  • Have participated in a research study involving intensive blood sampling or have donated blood within the past two months
  • Had an unplanned hospitalization in the last 6 months or two or more unplanned hospitalizations in the last 2 years.
  • Are taking prescription medications, that may interfere with the metabolism of the study drugs (e.g., inhibitors or inducers of CYP3A4/5 or CYP2C19 or those that will displace protein binding of tacrolimus/cannabidiol). Interactions will be screened according to the Flockhart table.
  • Are taking over-the-counter medications, herbal or dietary supplements, and alternative medicines that may interfere with the metabolism of the study drugs (e.g., inhibitors or inducers of CYP3A4/5 or CYP2C19 or those that will displace protein binding of tacrolimus/cannabidiol) that the subject is unwilling or unable to stop over the course of the study. Interactions will be screened according to the Flockhart table.
  • Are students under supervision of any of the study investigators.
  • Cannot commit the time requested for this study.
  • Have a known CYP3A4 *22/*22 genotype

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: CYP3A5 expressers without chronic kidney disease
Drug: Tacrolimus single dose
5 mg once
Other Names:
  • Period 1
Drug: Epidiolex single dose
Epidiolex 5 mg/kg
Other Names:
  • Period 2
Drug: Epidiolex steady-state and tacrolimus single dose
Epidiolex at up to 5 mg/kg twice daily (for 14 days) and tacrolimus 5 mg once on day 12 of period
Other Names:
  • Period 3
Active Comparator: CYP3A5 non-expressers without chronic kidney disease
Drug: Tacrolimus single dose
5 mg once
Other Names:
  • Period 1
Drug: Epidiolex single dose
Epidiolex 5 mg/kg
Other Names:
  • Period 2
Drug: Epidiolex steady-state and tacrolimus single dose
Epidiolex at up to 5 mg/kg twice daily (for 14 days) and tacrolimus 5 mg once on day 12 of period
Other Names:
  • Period 3
Active Comparator: CYP3A5 expressers with chronic kidney disease
Drug: Tacrolimus single dose
5 mg once
Other Names:
  • Period 1
Drug: Epidiolex single dose
Epidiolex 5 mg/kg
Other Names:
  • Period 2
Drug: Epidiolex steady-state and tacrolimus single dose
Epidiolex at up to 5 mg/kg twice daily (for 14 days) and tacrolimus 5 mg once on day 12 of period
Other Names:
  • Period 3
Active Comparator: CYP3A5 non-expressers with chronic kidney disease
Drug: Tacrolimus single dose
5 mg once
Other Names:
  • Period 1
Drug: Epidiolex single dose
Epidiolex 5 mg/kg
Other Names:
  • Period 2
Drug: Epidiolex steady-state and tacrolimus single dose
Epidiolex at up to 5 mg/kg twice daily (for 14 days) and tacrolimus 5 mg once on day 12 of period
Other Names:
  • Period 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The AUC0-Infinity ratio of tacrolimus with cannabidiol divided by tacrolimus alone
Time Frame: 27 days
The primary outcome is the AUC0-Infinity ratio of tacrolimus with cannabidiol divided by tacrolimus alone between CYP3A5 expressers and non-expressers in subjects with and without chronic kidney disease (CKD). Subjects with and without CKD will be analyzed separately.
27 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Immune cell distribution and signaling as measured by scRNA sequencing
Time Frame: 27 days
Immune cell distribution and signaling as measured by scRNA sequencing. The hypothesis tested is that cannabidiol will induce T regulatory lymphocytes (Tregs) and reduce overall cytokine signaling as compared to tacrolimus alone. Period 1 and Period 3 will be compared.
27 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Indiana University

Collaborators

The National Center for Complementary and Integrative Health

Investigators

  • Principal Investigator: Michael Eadon, MD, Indiana University School of Medicine
  • Principal Investigator: Zeruesenay Desta, PhD, Indiana University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 31, 2022

Primary Completion (Estimated)

October 1, 2028

Study Completion (Estimated)

October 1, 2028

Study Registration Dates

First Submitted

August 3, 2022

First Submitted That Met QC Criteria

August 3, 2022

First Posted (Actual)

August 5, 2022

Study Record Updates

Last Update Posted (Actual)

April 8, 2024

Last Update Submitted That Met QC Criteria

April 5, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 12763
  • 5R01AT011463-02 (U.S. NIH Grant/Contract)

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

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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