TIP-002 - DRUG-GENE-NUTRACEUTICAL INTERACTIONS OF CANNABIDIOL AND TACROLIMUS.

G. So, Y. Cheng, J. Stuart, K. McClara, J. Lu, D. Gisch, T. Beamon, Z. Cowsert, Z. Desta, M. Eadon; Indiana University, Indianapolis, IN, USA.

Background: Tacrolimus is frequently used to prevent organ rejection and is nephrotoxic if dosed above its narrow therapeutic index. Limited options exist for pain control in transplant patients with chronic kidney disease (CKD). Cannabidiol is an option, but it has the potential to inhibit cytochrome P450 (CYP) 3A4/5-mediated clearance of tacrolimus and to further suppress immunity. This calls for a clinical trial studying the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of co-administrating cannabidiol and tacrolimus.

Methods: This is an open-label, three-period, fixed sequence, single-center study in adults with or without CKD (NCT05490511). Those with safety concerns, positive drug screen of cannabis, or CYP3A4*22/*22 genotype are excluded. Eligible subjects will receive a single dose of tacrolimus (5 mg) and cannabidiol (5 mg/kg) in Period 1 and 2, respectively. In Period 3, they will receive twice daily cannabidiol (up to 10 mg/kg/day) in a titration period, followed by a single dose of tacrolimus (5 mg) while at cannabidiol steady state. The PK parameters of tacrolimus, cannabidiol, and their respective metabolites will be obtained via standard noncompartmental method, which include area under the curve (AUC), maximal concentration (Cmax), time to Cmax (Tmax), and apparent oral clearance (CLPO), and terminal elimination half-life (t1/2). In Period 2 and 3, lymphocytes will be collected in a subset of subjects to study the PD immunosuppressive interactions of cannabidiol and tacrolimus with a proliferation assay. The cultured lymphocytes will undergo single-cell sequencing to detect transcriptional changes before and after cannabidiol administration. Eleven subjects have completed the study; recruitment is ongoing with a goal of 60 subjects.

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Design: While the literature has demonstrated that cannabidiol inhibits CYP3A5, it was not tested in a drug product containing cannabidiol upon approval by the Food and Drug Administration (FDA). The FDA could change the drug label based on the results of this trial. Another novelty is the use of cell sequencing approach in the clinical trial to explore the transcriptional mechanism of immunosuppression by cannabidiol that is not well characterized. It will inspire future clinical trials with similar molecular phenotype.