Pharmacokinetic Drug‐Drug Interaction With Coadministration of Cannabidiol and Everolimus in a Phase 1 Healthy Volunteer Trial

• Published in: Clinical pharmacology in drug development Vol. 12; no. 9; pp. 911 - 919
• Main Authors: Wray, Louise, Berwaerts, Joris, Critchley, David, Hyland, Kerry, Chen, Cuiping, Thai, Ching, Tayo, Bola
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2023
• Subjects: antiseizure medication; Cannabidiol; Drug dosages; epilepsy; Inhibitor drugs; mTOR inhibitor; Pharmacokinetics; P‐glycoprotein; Tuberous sclerosis; tuberous sclerosis complex; P-glycoprotein; epilepsy; mTOR inhibitor; antiseizure medication; tuberous sclerosis complex
• ISSN: 2160-763X; 2160-7648; 2160-7648
• DOI: 10.1002/cpdd.1262

When highly purified cannabidiol (CBD; Epidiolex) and the mammalian target of rapamycin inhibitor everolimus are used concomitantly in the treatment of tuberous sclerosis complex, there is evidence of a pharmacokinetic (PK) interaction, leading to increased everolimus systemic exposure. We evaluated the effect of steady‐state CBD exposure following multiple clinically relevant CBD doses on everolimus PK in healthy adult participants in a single‐center, fixed‐sequence, open‐label, phase 1 study. All participants received oral everolimus 5 mg on day 1, followed by a 7‐day washout. On days 9–17, participants received CBD (100 mg/mL oral solution) at 12.5 mg/kg in the morning and evening. On the morning of day 13, participants also received a single dose of oral everolimus 5 mg. Medications were taken 30 or 45 minutes (morning or evening dose) after starting a standardized meal. Maximum concentration and area under the concentration‐time curve (AUC) from time of dosing to the last measurable concentration and extrapolated to infinity, of everolimus in whole blood were estimated using noncompartmental analysis, with geometric mean ratios and 90% confidence intervals for the ratios of everolimus dosed with CBD to everolimus dosed alone. A single dose of everolimus 5 mg was well tolerated when administered with multiple doses of CBD. Log‐transformed everolimus maximum concentration, AUC from time of dosing to the last measurable concentration, and AUC extrapolated to infinity values increased by ≈2.5‐fold, and everolimus half‐life remained largely unchanged in the presence of steady‐state CBD relative to everolimus dosed alone. Everolimus blood concentration monitoring should be strongly advised with appropriate dose reduction when coadministered with CBD.