GW Research Ltd, Cambridge, UK.
Epilepsia. 2020 Feb;61(2):267-277. doi: 10.1111/epi.16419. Epub 2020 Feb 3.
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).
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.
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.
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.
评估在健康成年人中，单次口服 750 毫克高纯度大麻二酚（CBD；美国的 Epidiolex 和欧洲的 Epidyolex；100 毫克/毫升口服溶液）植物源药物制剂，在高脂肪/高热量膳食（n=15）、低脂肪/低热量膳食（n=14）、全脂牛奶（n=15）或酒精（n=14）条件下，与禁食状态（n=29）相比的药代动力学（PK）和安全性。
在每个时期，在给药后 96 小时内采集血样，并通过液相色谱和串联质谱法进行评估。采用非房室分析方法，得出 CBD 及其主要代谢物的 PK 参数（最大观测血浆浓度[C ]、从零时到最后可定量浓度的血浆浓度-时间曲线下面积、从零时到无穷大的浓度-时间曲线下面积[AUC ]和最大血浆浓度时间[t ]）。
与禁食相比，高脂肪/高热量膳食使 CBD 的 AUC 和 C 分别增加了 3.8 倍和 5.2 倍。低脂肪/低热量膳食使 CBD 的 AUC 和 C 分别增加了 2.7 倍和 3.8 倍，与禁食相比，CBD 暴露程度也略有增加。同样，当给予全脂牛奶时，与禁食相比，AUC 和 C 分别增加了 2.4 倍和 3.1 倍。当给予酒精时，CBD 暴露程度适度增加，AUC 和 C 分别增加了 1.6 倍和 1.9 倍。在任何试验条件下，CBD t 和 t 与禁食状态相比，均无明显的临床相关影响。在 CBD 代谢物中也出现了相同的趋势，只是当 CBD 与酒精一起给药时，7-羧基大麻二酚 t 明显延长（14 小时禁食）。试验期间，PK 参数的个体间和个体内变异性为中度至高度。
高脂肪/高热量膳食对 CBD 和代谢物的暴露影响最大。低脂肪/低热量膳食、全脂牛奶或酒精也会增加 CBD 的暴露，但程度较小。试验期间，CBD 可耐受，无严重或严重不良事件。
