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

Epilepsia. 2020 Feb;61(2):267-277. doi: 10.1111/epi.16419. Epub 2020 Feb 3.

Abstract

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.

Keywords: alcohol; cannabidiol; cannabinoid; food effect; pharmacokinetics.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alcoholic Beverages*
  • Animals
  • Anticonvulsants / adverse effects
  • Anticonvulsants / pharmacokinetics*
  • Area Under Curve
  • Biological Availability
  • Biotransformation
  • Cannabidiol / adverse effects
  • Cannabidiol / pharmacokinetics*
  • Chromatography, High Pressure Liquid
  • Cross-Over Studies
  • Dietary Fats
  • Energy Intake
  • Female
  • Food-Drug Interactions
  • Half-Life
  • Humans
  • Male
  • Meals*
  • Middle Aged
  • Milk*
  • Tandem Mass Spectrometry
  • Young Adult

Substances

  • Anticonvulsants
  • Dietary Fats
  • Cannabidiol