Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy
Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy
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DOI：
10.1111/epi.16093
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发表时间：
2019-08-01
期刊：
影响因子：
5.6
通讯作者：
Leppik, Ilo E.
中科院分区：
文献类型：
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作者：
Birnbaum, Angela K.;Karanam, Ashwin;Leppik, Ilo E.
目的评价口服大麻二酚（CBD）胶囊在成人难治性癫痫患者中的药代动力学。方法入选了接受CBD治疗癫痫发作、每月癫痫发作≥ 4次且符合明尼苏达州大麻资格的定位相关顽固性癫痫患者。在空腹（不吃早餐）和进食（高脂肪840-860卡路里）条件下服用单剂量的99%纯CBD胶囊。在给药后0至72小时之间，在每种条件下进行血液采样以测定CBD血浆浓度，并通过经验证的液相色谱-质谱测定法进行测量。计算CBD药代动力学曲线，包括最大浓度（C-max）、从0至无穷大的曲线下面积（AUC（0-无穷大））和至最大浓度的时间（T-max）。计算进食和空腹状态之间对数转换的C-max和AUC（0-无穷大）比值的置信区间（CI）。收集癫痫发作和不良事件信息。结果8例患者完成研究。在进食状态下，平均C-max高14倍，AUC（0-无穷大）高4倍。餐后与空腹条件下C-max和AUC（0-无穷大）比值的90% CI分别为7.47-31.86和3.42-7.82。未观察到C-max和AUC（0-无穷大）的序列或阶段效应。未报告不良事件。将CBD作为胶囊而不是液体施用允许更精确地测定药代动力学参数，并且更能代表CBD吞咽产品。膳食中的脂肪含量可导致C-max和AUC（0-无穷大）显著增加，并可解释口服产品患者体内生物利用度和总体药物暴露的变异性。
Objective To evaluate the pharmacokinetics of a purified oral cannabidiol (CBD) capsule administered with and without food in adults with refractory epilepsy. Methods Adult patients who were prescribed CBD for seizures, had localization-related intractable epilepsy with >= 4 seizures per month, and qualified for Minnesota cannabis were enrolled. A single dose of 99% pure CBD capsules was taken under both fasting (no breakfast) and fed (high fat 840-860 calorie) conditions. Blood sampling for CBD plasma concentrations was performed under each condition between 0 and 72 hours post-dose and measured by a validated liquid chormatography-mass spectometry assay. CBD pharmacokinetic profiles including maximum concentration (C-max), area-under-the-curve from zero to infinity (AUC(0-infinity)), and time-to-maximum concentration (T-max) were calculated. The confidence intervals (CIs) for log-transformed C-max and AUC(0-infinity) ratios between fed and fasting states were calculated. Seizure and adverse events information was collected. Results Eight patients completed the study. On average C-max was 14 times and AUC(0-infinity) 4 times higher in the fed state. The 90% CI for the ratio of fed versus fast conditions for C-max and AUC(0-infinity) were 7.47-31.86 and 3.42-7.82, respectively. No sequence or period effect for C-max and AUC(0-infinity) was observed. No adverse events were reported. Significance Administering CBD as a capsule rather than a liquid allows for more precise determination of pharmacokinetics parameters and is more representative of CBD swallowed products. The fat content of a meal can lead to significant increases in C-max and AUC(0-infinity) and can account for variability in bioavailability and overall drug exposure within patients with oral products.