LB-009 - CANNABIDIOL INCREASES EXPOSURE OF TACROLIMUS IN HEALTHY VOLUNTEERS.

G. So¹, Y. Cheng¹, J. Stuart¹, K. McClara¹, J. Lu¹, D. Gisch¹, S. Koyama², T. Beamon¹, Z. Cowsert¹, Z. Desta¹, M. Eadon¹; ¹Indiana University, Indianapolis, IN, USA, ²Indiana University, IN, USA.

Background: One in seven Americans use cannabidiol-based or cannabis-derived products. The FDA drug label for cannabidiol (EPIDIOLEX®; Greenwich Biosciences, Carlsbad, CA) indicates the drug is a substrate of CYP3A, but not an inhibitor. We hypothesized that cannabidiol would inhibit CYP3A-mediated metabolism of tacrolimus (PROGRAF®; Astellas Pharma US, Deerfield, IL).

Methods: This is an open-label, three-period, fixed sequence, crossover ongoing study in healthy volunteers aged 18-65. In Period 1, subjects received a single dose of tacrolimus 5 mg orally. In Period 2, subjects received a single dose of cannabidiol 5 mg/kg orally. In Period 3, subjects received cannabidiol titrated up to 5 mg/kg twice daily for 12 days to reach steady state, followed by a single dose of tacrolimus 5 mg orally. Tacrolimus concentrations in whole blood were measured by UHPLC-MS/MS method. Pharmacokinetic parameters were calculated by noncompartmental analysis using Phoenix® WinNonlin® version 8.4 (Certara L.P. (Pharsight), Princeton, NJ). The study was actively enrolling on 9/14/2023, and data were analyzed on 11/3/2023.

Results: Data from 11 subjects who have completed all study phases are presented here. The maximum concentration (Cmax) of tacrolimus increased by 4.5-fold [from 8.9 ± 3.3 ng/mL without cannabidiol to 39.7 ± 14.1 ng/mL with cannabidiol (p < 0.00001)]. The area under the concentration versus time curve (AUC0-∞) increased 3.2-fold from 189.3 ± 57.2 ng*h/mL without cannabidiol to 603.9 ± 247.0 ng*h/mL with cannabidiol (p < 0.0001). No change in half-life was observed.

Conclusion: This is the first trial to demonstrate an interaction between cannabidiol and tacrolimus. Our data suggest the need for dose reduction of tacrolimus and frequent therapeutic dose monitoring in transplant patients taking cannabidiol concomitantly. Whether this observed interaction occurred due to inhibition of CYP3A4/5 in the liver and/or intestine or intestinal drug transporters (e.g., p-glycoprotein) remains to be elucidated.