Cannabidiol + Tacrolimus for Transplant Rejection
Recruiting in Palo Alto (17 mi)
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.12345
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.12367
Research Team
ME
Michael Eadon, MD
Principal Investigator
Indiana University School of Medicine
ZD
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.
See 4 more
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.
See 20 more
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 OverviewThe 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
4Treatment groups
Active Control
Group I: CYP3A5 expressers without chronic kidney diseaseActive Control3 Interventions
Group II: CYP3A5 non-expressers without chronic kidney diseaseActive Control3 Interventions
Group III: CYP3A5 expressers with chronic kidney diseaseActive Control3 Interventions
Group IV: CYP3A5 non-expressers with chronic kidney diseaseActive Control3 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
IU Health University HospitalIndianapolis, IN
Loading ...
Who Is Running the Clinical Trial?
Indiana University
Lead Sponsor
Trials
1063
Patients Recruited
1,182,000+
The National Center for Complementary and Integrative Health
Collaborator
Trials
1
Patients Recruited
70+
References
Drug interactions with tacrolimus. [2018]Tacrolimus is a drug for which therapeutic drug monitoring is recommended. The existence of a wide variety of potential drug interactions further supports the current strategy of measuring whole blood tacrolimus concentrations in transplanted patients. Cytochrome P450 (CYP)3A, the major phase I metabolising enzyme in humans, and the multi-drug efflux pump, P-glycoprotein, are present at high levels in the villus tip of enterocytes in the gastrointestinal tract. Oral bioavailability of tacrolimus can be increased by concomitant administration of inhibitors of either CYP3A or P-glycoprotein. CYP activity in the liver also influences tacrolimus concentrations. As a result, several drugs that are frequently being used in transplantation, such as corticosteroids and antifungal agents, will affect tacrolimus concentrations. Knowledge of such drug interactions is extremely important, as they may lead to clinically important under- or overexposure to tacrolimus, with acute rejection episodes or serious toxicity as a result.
Tacrolimus: a new immunosuppressive agent. [2019]The mechanism of action, pharmacokinetics, drug interactions, clinical efficacy, and adverse effects of tacrolimus, a newly approved immunosuppressant drug for use in the prophylaxis of organ rejection after transplantation, are reviewed. Tacrolimus prevents rejection of the transplanted organ by inhibiting the expression of interleukin-2 in T cells and inhibiting T-cell growth and proliferation. Bioavailability after oral administration is 5-67%, and the half-life is 4-41 hours. Tacrolimus is extensively metabolized by cytochrome P-450 3A4 isoenzyme, resulting in several known drug interactions. Most experience with tacrolimus has been at one institution, where clinical trials have been conducted in liver, kidney, heart, lung, and intestinal transplantation. Clinical trials have shown that tacrolimus is an effective alternative to cyclosporine for both primary immunosuppression and rescue therapy in liver transplant patients. Fewer reports have been published regarding tacrolimus use in other types of transplantation, but the results show that tacrolimus may be a useful alternative to cyclosporine. The major adverse effects of tacrolimus therapy are nephrotoxicity and neurotoxicity. Tacrolimus is an effective alternative to cyclosporine as a primary immunosuppressant in the prevention of organ rejection and may reduce the incidence of rejection after organ transplantation.
Immunosuppressive drug therapy--biopharmaceutical challenges and remedies. [2018]The most commonly used immunosuppressive drugs (ISDs) which can prevent rejection of transplanted organs include cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus and everolimus. The clinical efficacy of these drugs is greatly influenced by their in vivo performance. Various pharmacokinetic and toxicological constraints limit their therapeutic activity which is a matter of serious concern.
Topical tacrolimus and steroids modulate T cells in acute rejection of hand allotransplantation: Two case reports. [2021]Acute rejection is not uncommon after vascularized composite allotransplantation. We reported the effects of adjunctive topical immunosuppressant with topical tacrolimus (Protopic®) and steroid cream (Clobetasol®) in the management of acute rejection in two hand transplantation patients. Case 1 is a 45-year-old male with distal forearm deficit 4 years ago and Case 2 is a 30-year-old male with a proximal forearm deficiency 2 years ago, respectively. Both of them suffered from occupational accident and received hand allotransplantation. Induction was performed with antithymocyte globulins and methylprednisolone. Maintenance therapy consisted of tacrolimus (FK506), mycophenolate mofetil, and prednisone. Both cases experienced acute rejection, which we treated with topical tacrolimus and Clobetasol for 2 weeks, combined with systemic immunosuppressant maintenance therapy without adding pulse-steroid therapy. Clinically, both cases recovered after adjunctive treatments. The skin biopsies showed significantly decreased perivascular lymphocyte infiltration after topical treatment. Immunohistochemical staining showed that CD3+ T-cells and CD20+ B-cells were suppressed in the recovery phase. FoxP3-positive regulatory T cells were increased after treatment. Topical tacrolimus and Clobetasol as an adjunctive treatment with maintenance systemic immunosuppressives may be useful to control acute rejection, which correlated with modulation of lymphocyte activation, especially T cells. The treatment needs further investigation with gaining more comparable data.
Newer immunosuppressive drugs: a review. [2022]In recent years, many new immunosuppressive drugs have been discovered and developed for clinical use in transplantation. This review focuses on those drugs (leflunomide, mycophenolate mofetil, sirolimus, tacrolimus) that have been shown to have immunosuppressive activity in patients. Different anti-interleukin-2 receptor antibodies are also reviewed as an example of a resurgence of development in the area of monoclonal antibodies. The price for reducing the incidence of allograft rejection by improved immunosuppression was thought to be a proportional increase in the incidence of infection and malignancy. Data from Phase III clinical trials of new immunosuppressants, however, show a statistically significant reduction in the incidence of acute rejection produced by these new drugs, which has not been accompanied by increases in infection and malignancy rates. The wide array of new drugs offers the opportunity to use combinations that block different pathways of immune activation while at the same time selecting drug combinations with nonoverlapping toxicity profiles so that doses of each single drug can be reduced below toxicity levels. The immunosuppressive therapy for patients can be tailored according to their individual needs.
[Clinical pharmacokinetics and therapeutic monitoring of tacrolimus]. [2013]Tacrolimus (FK 506) is a new macrocyclic lactone immunosuppressant which possesses similar but more potent immunosuppressive properties compared with cyclosporin. It is able to inhibit T cell proliferation and the production of interleukine 2 (and other growth promoting cytokines). A major interest of tacrolimus is that it can be used as a rescue therapy since clinical trials have demonstrated its ability to be effective in some patients who develop rejection episodes refractory to current regimens, including corticosteroids. Tacrolimus is highly bound to erythrocytes and is largely metabolized, primarily in the liver, by Cyt P450 3A4. Its excretion pathway concerns the bile almost exclusively. Like cyclosporin, the drug is associated with a range of adverse effects including nephrotoxicity, neurotoxicity and diabetes. Tacrolimus also exhibits a large inter- and intra-individual variability of its pharmacokinetics. Because of this variability and the narrow therapeutic index of tacrolimus, monitoring of tacrolimus blood concentrations would be useful for optimization of therapy. However, even if we know that by maintaining the residual blood concentration under 15 micrograms/l it is possible to reduce dramatically the occurrence of adverse effects, we still have not determined the threshold value of clinical efficacy. This will be important for current and future clinical pharmacology investigations with tacrolimus.
Clinically significant drug interactions with new immunosuppressive agents. [2018]Tacrolimus (FK506), mycophenolate mofetil, sirolimus (rapamycin), gusperimus, and monoclonal antibody preparations are new immunosuppressive agents, some of which are already approved for clinical use, while others are currently undergoing clinical trials. The present article provides an overview of adverse drug interactions between these immunosuppressants and other drugs which may be used concomitantly. Preliminary data suggest that a pharmacodynamic interaction can occur between tacrolimus and nonsteroidal anti-inflammatory drugs, associated with an increased risk of nephrotoxicity. Erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol have been shown to increase tacrolimus blood concentrations, while rifampicin (rifampicin) was found to decrease tacrolimus blood concentrations. Evidence from experimental studies suggest that several other drugs also known to affect cytochrome P450 activity may have significant effects on the pharmacokinetics of tacrolimus. On the other hand, tacrolimus itself may inhibit the metabolism of coadministered drugs. This interaction may be attributed to the enhanced renal impairment which has been observed in patients treated with tacrolimus and cyclosporin. The bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, has been reported to be reduced by aluminium/magnesium hydroxide-containing antacids and cholestyramine. Mycophenolic acid, sirolimus and gusperimus may impair bone marrow function and this adverse effect may be enhanced by concomitant administration of other myelosuppressive drugs. There is some evidence that coadministered sirolimus and cyclosporin cause an increase in each other's blood concentrations. An increased risk of central nervous system adverse effects has been described following the combined use of indomethacin and the monoclonal antibody muromonab CD3 (OKT3).