Project Summary/Abstract Most solid organ recipients are prescribed tacrolimus to prevent rejection and maintain allograft function. The overall goal of this study is to assess the safety of cannabidiol (CBD) when co-administered with tacrolimus. The proposed studies will comprehensively define the pharmacokinetic interactions of cannabidiol, tacrolimus, and CYP3A5. Cannabidiol is a potent inhibitor of the CYP3A4 and CYP3A5 enzymes and CYP3A5 is a polymorphic enzyme with expression differences across populations. During the proposed experimentation, we will uncover whether the metabolism of CBD is affected by CYP3A5 genotype. We will also determine whether a drug-drug interaction (DDI) exists between cannabidiol and tacrolimus, an immunosuppressant metabolized by CYP3A4 and CYP3A5. If a DDI is identified, we will determine whether this DDI is more potent in CYP3A5 normal metabolizers. We hypothesize that CBD will cause a drug-drug interaction requiring a much larger dose reduction of tacrolimus in CYP3A5 expressors than non-expressors. In aim 1, we will test this hypothesis in a series of PK studies in individuals with different CYP3A5 genotypes. The primary outcome is the tacrolimus area-under-the-curve (AUC) in CYP3A5 expressors and non-expressors while taking CBD at a steady state concentration. CBD may also lead to pharmacodynamic effects relevant to transplant recipients, independent of tacrolimus concentration. Thus, in aim 2, we investigate the pharmacodynamic interactions of CBD and tacrolimus in the immune system. We will use sensitive phenotypes such as immune cell distribution and cell expression signatures derived from single cell sequencing. The information gleaned in these experiments is important as it is expected that this work will help practitioners advise their patients, including transplant recipients, whether drug interactions are present or whether it is safe to take cannabidiol.

Project Narrative 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.