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

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 [C ], 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 [AUC ], and time to maximum plasma concentration [t ]) of CBD and its major metabolites were derived using noncompartmental analysis.

Results: CBD exposure increased by 3.8-fold for AUC and 5.2-fold for C 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 AUC and a 3.8-fold increase in C . Similarly, when dosed with whole milk, CBD exposure increased versus fasted by 2.4-fold for AUC and 3.1-fold for C . Modest elevations in CBD exposure occurred when it was dosed with alcohol: 1.6-fold for AUC and 1.9-fold for C . No clinically relevant effect of any test condition on CBD t or t versus the fasted state was apparent. The same trend was seen for the CBD metabolites, except that 7-carboxy-cannabidiol t 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.