Cannabidiol + Tacrolimus for Transplant Rejection

Overseen By Kelsey McClara

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Indiana University

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

Disqualifiers: Pregnancy, Seizure disorder, Liver dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 27 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how two drugs, Epidiolex (a form of cannabidiol) and Tacrolimus (an immunosuppressant), can help prevent transplant rejection. The goal is to determine the right doses to improve long-term success for organ transplant recipients. The trial includes different groups, such as those with normal kidney function and those with kidney disease, to assess how these conditions affect treatment. This trial may suit individuals without a current organ transplant who are willing to stop taking certain medications and supplements that could interfere with the study drugs. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking medical research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that cannabidiol (the active ingredient in Epidiolex) and tacrolimus can interact, altering how each drug functions in the body. For transplant recipients, this interaction might require dose adjustments to ensure proper efficacy.

Reports have noted side effects, such as changes in mental state, when tacrolimus is used with cannabis. These reports differ from studies focusing on Epidiolex, a purified form of cannabidiol approved by the FDA for treating seizures.

Previous research on tacrolimus alone indicates that its blood levels can be unpredictable immediately after a transplant, necessitating close monitoring. As this study is in its early stages, the primary goal is to understand the interaction between these two drugs, aiding doctors in making safer dose adjustments in the future.

In summary, while the interaction between Epidiolex and tacrolimus has been studied, further research will help ensure safety for transplant patients. Participants in this trial will contribute valuable information on optimizing the use of these medications together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cannabidiol (Epidiolex) and tacrolimus for preventing transplant rejection because it introduces a novel approach to managing this condition. Unlike traditional treatments, which often rely solely on immunosuppressants like tacrolimus, this combination incorporates cannabidiol, known for its anti-inflammatory properties. This dual approach aims to enhance the efficacy of tacrolimus while potentially reducing its side effects, offering a more balanced and effective solution. The use of cannabidiol could also address inflammation in a way that current options do not, providing a fresh angle in the fight against transplant rejection.

What evidence suggests that this trial's treatments could be effective for transplant rejection?

In this trial, participants will receive a combination of cannabidiol (CBD) and tacrolimus to study their effects on transplant rejection. Research has shown that CBD can raise tacrolimus levels, a drug used to prevent organ rejection, by altering its metabolism in the body. This suggests that CBD might allow for lower doses of tacrolimus to remain effective. In some kidney transplant patients, adding CBD helped with pain control and was well-tolerated. Studies also indicate that CBD can triple tacrolimus levels. This suggests that using them together could effectively prevent transplant rejection, with careful dose adjustments. ^{1 2 3 5 6}

Who Is on the Research Team?

Zeruesenay Desta, PhD

Principal Investigator

Indiana University School of Medicine

Michael Eadon, MD

Principal Investigator

Indiana University School of Medicine

Are You a Good Fit for This Trial?

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 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.

My kidney function is good and I have low protein in my urine.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Epidiolex
• Tacrolimus

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.

How Is the Trial Designed?

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

Epidiolex is already approved in United States, European Union for the following indications:

Approved in United States as Epidiolex for:

• Seizures associated with Lennox-Gastaut syndrome
• Seizures associated with Dravet syndrome
• Seizures associated with tuberous sclerosis complex

Approved in European Union as Epidyolex for:

• Seizures associated with Lennox-Gastaut syndrome
• Seizures associated with Dravet syndrome

Who Is Running the Clinical Trial?

Indiana University

Lead Sponsor

Trials

1,063

Recruited

1,182,000+

The National Center for Complementary and Integrative Health

Collaborator

Trials

1

Recruited

70+

National Center for Complementary and Integrative Health (NCCIH)

Collaborator

Trials

886

Recruited

677,000+

Published Research Related to This Trial

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]

Recent immunosuppressive drugs like leflunomide, mycophenolate mofetil, sirolimus, and tacrolimus have significantly reduced the incidence of acute allograft rejection in transplant patients without increasing the rates of infections or malignancies, based on Phase III clinical trial data.

The development of these new drugs allows for tailored immunosuppressive therapy, enabling combinations that target different immune pathways while minimizing toxicity, thus improving patient safety and treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Newer immunosuppressive drugs: a review. Gummert, JF., Ikonen, T., Morris, RE.[2022]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9772032/

Cannabis Use and Heart Transplantation - PubMed Central CBD can raise tacrolimus levels by inhibiting CYP3A4 and P-glycoprotein. Tacrolimus toxicity with cannabinoids consumption has been limited to ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05490511

Study Details | NCT05490511 | Drug-gene-nutraceutical ... The primary outcome is the AUC0-Infinity ratio of tacrolimus with cannabidiol divided by tacrolimus alone between CYP3A5 expressers and non-expressers in ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11806196/

Inhibition of Tacrolimus Metabolism by Cannabidiol and Its ... In a case study, 86% of kidney transplant recipients had at least partial pain control and good tolerability with CBD in the first 15 days [27].

4. ascpt.onlinelibrary.wiley.com ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.3504?af=R

A Phase I Trial of the Pharmacokinetic Interaction Between ... This study demonstrates that cannabidiol increases tacrolimus exposure. Our data suggest the need for dose reduction in tacrolimus and frequent therapeutic ...

5. journals.lww.com journals.lww.com/transplantjournal/fulltext/2021/02000/the_clinical_conundrum_of_cannabis__current.9.aspx

The Clinical Conundrum of Cannabis: Current Practices ... Most recently, CBD use in a renal transplant recipient (RTR) resulted in approximately a 3-fold increase in dose-normalized tacrolimus concentrations ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/050708s055,010115s007lbl.pdf

Prograf (tacrolimus) capsules, for oral use - accessdata.fda.gov Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation. The relative risks of ...