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.
<h4>Objective</h4>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).<h4>Methods</h4>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<sub>max</sub> ], 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<sub>0-∞</sub> ], and time to maximum plasma concentration [t<sub>max</sub> ]) of CBD and its major metabolites were derived using noncompartmental analysis.<h4>Results</h4>CBD exposure increased by 3.8-fold for AUC<sub>0-∞</sub> and 5.2-fold for C<sub>max</sub> 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<sub>0-∞</sub> and a 3.8-fold increase in C<sub>max</sub> . Similarly, when dosed with whole milk, CBD exposure increased versus fasted by 2.4-fold for AUC<sub>0-∞</sub> and 3.1-fold for C<sub>max</sub> . Modest elevations in CBD exposure occurred when it was dosed with alcohol: 1.6-fold for AUC<sub>0-∞</sub> and 1.9-fold for C<sub>max</sub> . No clinically relevant effect of any test condition on CBD t<sub>max</sub> or t<sub>½</sub> versus the fasted state was apparent. The same trend was seen for the CBD metabolites, except that 7-carboxy-cannabidiol t<sub>max</sub> 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.<h4>Significance</h4>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.