Abstracts

Rationale: Everolimus is an mTOR inhibitor used in patients with tuberous sclerosis complex (TSC). Highly purified CBD has recently been FDA-approved for the treatment of seizures in patients with TSC and may be used concomitantly with everolimus. Previous case reports and retrospective studies suggested blood exposure of mTOR inhibitors increased when administered concomitantly with CBD. Given the potential pharmacokinetic (PK) drug-drug interaction, we conducted a fixed-sequence open-label phase 1 trial to assess the effect of multiple doses of CBD on the PK parameters of a single dose of everolimus in healthy volunteers.

Methods: The trial duration was ~63 days: screening (up to 28 days), treatment (18 days), and safety follow-up period (14 days [+3 days]). On Day 1 subjects received 5 mg of everolimus (oral tablet) in the morning, 30 minutes after a standardized meal, followed by a 7-day washout period (Days 2–8). On Days 9–17, subjects received 12.5 mg/kg twice daily (b.i.d.) plant-derived highly purified CBD (Epidiolex®; 100 mg/mL in oral solution) in the morning and evening, 30 and 45 minutes after a standardized meal, respectively. On Day 13, subjects received 5 mg of everolimus concomitant with their morning CBD dose. On Day 18 subjects received their final morning CBD dose. Subjects were assessed for everolimus PK parameters (C_max, maximum concentration; AUC_0-last and AUC_0-∞, area under the curve from administration to last observation and to infinity; t_max and t_½, time to maximum concentration and terminal half-life) up to 120 hours after each everolimus dose, and for safety parameters throughout the trial.

Results: A total of 16 male healthy volunteers were enrolled, with a mean age of 28 years (range: 20–45); 15 completed (1 lost to follow-up). Everolimus blood exposure increased with coadministration of CBD compared with everolimus alone; the geometric mean ratio for test (Day 13) vs. reference (Day 1) conditions was similar across C_max (2.5, 90% CI [2.1, 2.9]), AUC_0-last (2.6, 90% CI [2.2, 2.9]), and AUC_0-∞ (2.5, 90% CI [2.2, 2.8]). Small changes in everolimus t_max and t_½ were observed after coadministration with CBD compared with everolimus alone: t_max median difference 0.8, 90% CI (0.00, 1.5); and t_½ mean (SD) 33.2 (±4.2) hours vs. 40.0 (±5.1) hours. Overall, adverse events (AEs) were reported in 10 subjects (63%). All AEs were mild and resolved spontaneously.

Conclusions: Everolimus blood exposure following a single 5 mg everolimus dose increased ~2.5-fold when given at CBD steady state (12.5 mg/kg b.i.d.) in healthy volunteers. A single dose of everolimus was well tolerated when administered alone or with multiple doses of CBD. Results suggest that CBD enhances the absorption of everolimus administered as an oral tablet formulation, without apparent effect on systemic clearance. Thus, adjustments in everolimus dose should be considered when co-administered orally with CBD.

Funding: Please list any funding that was received in support of this abstract.: GW Research Ltd.