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-max], 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(0-infinity)], and time to maximum plasma concentration [t(max)]) of CBD and its major metabolites were derived using noncompartmental analysis. Results CBD exposure increased by 3.8-fold for AUC(0-infinity) and 5.2-fold for C-max 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(0-infinity) and a 3.8-fold increase in C-max. Similarly, when dosed with whole milk, CBD exposure increased versus fasted by 2.4-fold for AUC(0-infinity) and 3.1-fold for C-max. Modest elevations in CBD exposure occurred when it was dosed with alcohol: 1.6-fold for AUC(0-infinity) and 1.9-fold for C-max. No clinically relevant effect of any test condition on CBD t(max) or t(1/2) versus the fasted state was apparent. The same trend was seen for the CBD metabolites, except that 7-carboxy-cannabidiol t(max) 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.