Cannabidiol + Tacrolimus for Transplant Rejection

Overseen by Zeruesenay Desta, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Indiana University

Must not be taking: Sedatives, Immunosuppressants, CYP3A4/5 inhibitors

Disqualifiers: Pregnancy, Seizure disorder, Liver dysfunction, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial aims to understand how CBD, a cannabis compound, interacts with tacrolimus, a drug used by organ transplant patients to prevent rejection. Researchers will study these interactions to see if CBD affects the safety and effectiveness of tacrolimus. Tacrolimus is a strong medication used to prevent organ rejection in transplant patients, with precise dosing requirements. The goal is to help doctors adjust doses of both substances to improve patient health and long-term treatment success.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any prescription medications, over-the-counter medications, and herbal, dietary, and alternative supplements that may interact with the study drugs at least 2 weeks before the study starts and until it is completed.

What data supports the effectiveness of the drug combination of Cannabidiol and Tacrolimus for transplant rejection?

Tacrolimus is an effective drug for preventing organ rejection after transplantation, as it inhibits the growth of certain immune cells that can attack the transplanted organ. While there is no direct evidence for the combination with Cannabidiol, Tacrolimus has been shown to be a useful alternative to other immunosuppressants in transplant patients. ^{1 2 3 4 5}

How is the drug combination of Cannabidiol and Tacrolimus unique for transplant rejection?

This drug combination is unique because it combines Cannabidiol (CBD), known for its anti-inflammatory properties, with Tacrolimus, an immunosuppressant that prevents organ rejection by inhibiting T-cell growth. The combination may offer a novel approach by potentially enhancing the immunosuppressive effects while reducing inflammation, which is different from standard treatments that typically focus solely on immunosuppression. ^{1 2 3 6 7}

Research Team

Michael Eadon, MD

Principal Investigator

Indiana University School of Medicine

Zeruesenay Desta, PhD

Principal Investigator

Indiana University School of Medicine

Eligibility Criteria

This trial is for adults aged 18-65 with either healthy kidneys or chronic kidney disease, not on dialysis. Participants must avoid certain medications, supplements, and substances like tobacco and marijuana that affect the study drugs' metabolism for two weeks before and during the study. Pregnant or breastfeeding individuals, those with compromised liver function, a history of drug abuse or intolerance to study drugs are excluded.

Inclusion Criteria

I am between 18 and 65 years old.

I am willing to dedicate the necessary time for this study.

I have been deemed healthy enough to join based on my medical history, blood and urine tests, and EKG results.

Exclusion Criteria

I am allergic or have had bad reactions to tacrolimus or cannabidiol.

My liver tests show bilirubin or enzymes more than twice the normal limit.

I do not have ongoing stomach issues that affect how I absorb pills.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cannabidiol and tacrolimus to study drug-gene and drug-drug interactions

27 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Epidiolex (Cannabinoid)
• Tacrolimus (Immunosuppressant)

Trial Overview The trial investigates how cannabidiol (Epidiolex) interacts with tacrolimus in people who have received transplants. It aims to find safe dosing levels that could improve health outcomes by studying single doses of each drug alone and together at steady-state conditions.

Participant Groups

Group I: CYP3A5 expressers without chronic kidney disease Active Control 3 Interventions

Group II: CYP3A5 non-expressers without chronic kidney disease Active Control 3 Interventions

Group III: CYP3A5 expressers with chronic kidney disease Active Control 3 Interventions

Group IV: CYP3A5 non-expressers with chronic kidney disease Active Control 3 Interventions

Who Is Running the Clinical Trial?

Indiana University

Lead Sponsor

Trials

1,063

Recruited

1,182,000+

Alan Palkowitz

Indiana University

Chief Executive Officer since 2020

PhD in Chemistry from Indiana University

David Ingram

Indiana University

Chief Medical Officer since 2020

MD from Indiana University School of Medicine

The National Center for Complementary and Integrative Health

Collaborator

Trials

1

Recruited

70+

Findings from Research

Tacrolimus requires careful therapeutic drug monitoring due to its narrow therapeutic range and the potential for significant drug interactions that can affect its concentration in the body.

Inhibitors of CYP3A or P-glycoprotein can increase the oral bioavailability of tacrolimus, making it crucial for healthcare providers to be aware of other medications, like corticosteroids and antifungal agents, that may alter tacrolimus levels and lead to serious complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug interactions with tacrolimus. van Gelder, T.[2018]

Tacrolimus is an effective immunosuppressant that prevents organ rejection after transplantation by inhibiting interleukin-2 expression in T cells, making it a viable alternative to cyclosporine, especially in liver transplant patients.

While tacrolimus shows promise in various types of transplantation, it is associated with significant adverse effects, particularly nephrotoxicity and neurotoxicity, which need to be monitored closely during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tacrolimus: a new immunosuppressive agent. Kelly, PA., Burckart, GJ., Venkataramanan, R.[2019]

Immunosuppressive drugs (ISDs) like cyclosporine and tacrolimus face significant challenges in absorption due to poor solubility, gut metabolism, and hepatic first-pass effects, which can limit their therapeutic effectiveness.

Novel formulation strategies, including lipid nanocarriers and the integration of P-glycoprotein and CYP inhibitors, may enhance the bioavailability and efficacy of ISDs, potentially improving patient outcomes in organ transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppressive drug therapy--biopharmaceutical challenges and remedies. Khan, S., Khan, S., Baboota, S., et al.[2018]

Topical treatments with tacrolimus and Clobetasol were effective in managing acute rejection in two hand transplantation patients, leading to clinical recovery without the need for additional steroid therapy.

The treatment resulted in a significant reduction of lymphocyte infiltration in skin biopsies, indicating that these topical immunosuppressants can modulate T-cell activation and improve outcomes in acute rejection cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical tacrolimus and steroids modulate T cells in acute rejection of hand allotransplantation: Two case reports. Chen, YT., Huang, SC., Chen, CC., et al.[2021]

Tacrolimus is a potent immunosuppressant that can effectively treat patients experiencing rejection episodes that do not respond to standard therapies, including corticosteroids, making it a valuable rescue therapy option.

Due to its narrow therapeutic index and significant variability in how individuals metabolize the drug, careful monitoring of blood concentrations is essential to minimize adverse effects while determining the optimal dosage for clinical efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical pharmacokinetics and therapeutic monitoring of tacrolimus]. Garraffo, R.[2013]

Tacrolimus can interact with nonsteroidal anti-inflammatory drugs, increasing the risk of kidney damage, and its blood levels can be affected by various medications, such as erythromycin and rifampicin, which can either increase or decrease its concentration.

Mycophenolate mofetil and sirolimus may impair bone marrow function, and their adverse effects can be worsened when taken with other drugs that suppress bone marrow, highlighting the importance of monitoring drug interactions in patients on these immunosuppressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinically significant drug interactions with new immunosuppressive agents. Mignat, C.[2018]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Drug interactions with tacrolimus. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Tacrolimus: a new immunosuppressive agent. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Immunosuppressive drug therapy--biopharmaceutical challenges and remedies. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Topical tacrolimus and steroids modulate T cells in acute rejection of hand allotransplantation: Two case reports. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Newer immunosuppressive drugs: a review. [2022]

6. France pubmed.ncbi.nlm.nih.gov

[Clinical pharmacokinetics and therapeutic monitoring of tacrolimus]. [2013]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Clinically significant drug interactions with new immunosuppressive agents. [2018]