A Phase I Trial of the Pharmacokinetic Interaction Between Cannabidiol and Tacrolimus

Abstract

One in six Americans uses cannabidiol-based or cannabis-derived products. Cannabidiol is a substrate of CYP3A, but its role as a potential CYP3A inhibitor remains unclear. We hypothesized that cannabidiol would inhibit CYP3A-mediated metabolism of tacrolimus. This report is an interim analysis of an open-label, three-period, fixed-sequence, crossover study in healthy participants. Participants first received a single dose of tacrolimus 5 mg orally. After washout, participants later received cannabidiol titrated to 5 mg/kg twice daily for 14 days to reach a steady state, followed by a second 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. Twelve participants completed all periods of the study. The maximum concentration (C_max) of tacrolimus increased 4.2-fold (P < 0.0001) with cannabidiol (40.2 ± 13.5 ng/mL) compared with without cannabidiol (9.85 ± 4.63 ng/mL). The area under the concentration-vs.-time curve (AUC_0-∞) increased 3.1-fold (P < 0.0001). No change in half-life (t_1/2) was observed. This study demonstrates that cannabidiol increases tacrolimus exposure. Our data suggest the need for dose reduction in tacrolimus and frequent therapeutic dose monitoring in transplant patients taking cannabidiol concomitantly. Whether this observed interaction occurred due to the inhibition of CYP3A4 and/or CYP3A5 in the liver, intestine, or both, or intestinal drug transporters (e.g., p-glycoprotein) during the first-pass elimination remains to be elucidated.

Figure 1

Study design. The study is a single‐center, open‐label, three‐period, fixed‐sequence, crossover phase I study. The interim analysis compared the area under the curve from time zero to infinity (AUC_0‐∞) ratio of tacrolimus between Period 1 (tacrolimus without cannabidiol) and Period 3 (tacrolimus with cannabidiol) in healthy volunteers. BID, twice daily; FU, follow up.

Figure 2

Pharmacokinetic profiles of tacrolimus in 12 healthy participants. The mean concentration–time plots of tacrolimus without cannabidiol (Tac; solid circles) and tacrolimus with cannabidiol (Tac + CBD; open circles) on a linear scale (left) and logarithmic scale (right) obtained from 12 healthy participants. The C _max increased 4.2‐fold (P < 0.0001; 95% confidence interval (95% CI) 2.93 to 5.95) and AUC_0‐∞ increased 3.1‐fold (P < 0.0001; 95% CI 2.62 to 3.60) with steady‐state cannabidiol use. Data points were plotted with geometric mean and 95% CI.

Figure 3

Tacrolimus pharmacokinetic parameters comparisons with and without cannabidiol (N = 12). The geometric mean and 95% confidence interval (95% CI) were plotted for each pharmacokinetic parameter except T _max, which was plotted as a median due to its ordinal nature. (a, b) Concomitant steady‐state cannabidiol led to increases in C _max and AUC_0‐∞. (c) No change in T _max was observed. (d, e) concomitant steady‐state cannabidiol led to decreases in CL/F and V _z/F. (f) No change in half‐life was observed. AUC_0‐∞, area under the curve from time zero to infinity; CBD, cannabidiol; CL/F, oral clearance; C _max, maximal blood concentration; Tac, tacrolimus; T _max, time to maximal blood concentration; t _1/2, terminal elimination half‐life; V _z/F, terminal phase distribution volume. ****P < 0.0001.

Figure 4

Cannabidiol steady‐state concentrations. Concentration–time plots of cannabidiol (5 mg/kg BID) at steady‐state were shown in (a) linear scale and (b) semi‐log scale. (c) Steady‐state trough concentrations of cannabidiol of Period 3. (d) The association of cannabidiol C _trough with tacrolimus AUC_0‐∞ fold change from Period 3 to Period 1 was assessed with simple linear regression with 95% confidence interval (95% CI) bands. AUC_0‐∞, area under the curve from time zero to infinity; BID, twice daily; CBD, cannabidiol; C _trough, trough concentration at steady state.