A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects

• Published in: Epilepsia (Copenhagen) Vol. 61; no. 2; pp. 267 - 277
• Main Authors: Crockett, Julie, Critchley, David, Tayo, Bola, Berwaerts, Joris, Morrison, Gilmour
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2020; John Wiley and Sons Inc
• Subjects: Adult; Aged; Alcohol; Alcoholic Beverages; Animals; Anticonvulsants - adverse effects; Anticonvulsants - pharmacokinetics; Area Under Curve; Biological Availability; Biotransformation; Cannabidiol; Cannabidiol - adverse effects; Cannabidiol - pharmacokinetics; cannabinoid; Cannabinoids; Chromatography, High Pressure Liquid; Cross-Over Studies; Dietary Fats; Energy Intake; Female; food effect; Food-Drug Interactions; Full‐length Original Research; Half-Life; Humans; Liquid chromatography; Male; Mass spectroscopy; Meals; Metabolites; Middle Aged; Milk; Pharmacokinetics; Tandem Mass Spectrometry; Young Adult; alcohol; cannabidiol; pharmacokinetics; food effect; cannabinoid
• ISSN: 0013-9580; 1528-1167; 1528-1167
• DOI: 10.1111/epi.16419

Objective The pharmacokinetics (PK) and safety of single oral 750‐mg doses of a plant‐derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the USA and Epidyolex in Europe; 100‐mg/mL oral solution) were assessed in healthy adults following a high‐fat/calorie meal (n = 15), a low‐fat/calorie meal (n = 14), whole milk (n = 15), or alcohol (n = 14), relative to the fasted state (n = 29). Methods Blood samples were collected until 96 hours postdose in each period and evaluated by liquid chromatography and tandem mass spectrometry. PK parameters (maximum observed plasma concentration [Cmax], area under the plasma concentration‐time curve from time zero to the last observed quantifiable concentration, area under the concentration‐time curve from time zero to infinity [AUC0‐∞], and time to maximum plasma concentration [tmax]) of CBD and its major metabolites were derived using noncompartmental analysis. Results CBD exposure increased by 3.8‐fold for AUC0‐∞ and 5.2‐fold for Cmax when CBD was administered with a high‐fat/calorie meal versus fasted. To a lesser extent, a low‐fat/calorie meal enhanced CBD exposure versus fasted with a 2.7‐fold increase in AUC0‐∞ and a 3.8‐fold increase in Cmax. Similarly, when dosed with whole milk, CBD exposure increased versus fasted by 2.4‐fold for AUC0‐∞ and 3.1‐fold for Cmax. Modest elevations in CBD exposure occurred when it was dosed with alcohol: 1.6‐fold for AUC0‐∞ and 1.9‐fold for Cmax. No clinically relevant effect of any test condition on CBD tmax or t½ versus the fasted state was apparent. The same trend was seen for the CBD metabolites, except that 7‐carboxy‐cannabidiol tmax was considerably longer when CBD was administered with alcohol (14 vs 4 hours fasted). Inter‐ and intrasubject variability in PK parameters was moderate to high during the trial. Significance CBD and metabolite exposures were most affected by a high‐fat/calorie meal. CBD exposures also increased with a low‐fat/calorie meal, whole milk, or alcohol, but to a lesser extent. CBD was tolerated, and there were no severe or serious adverse events during the trial.