Brstilo Lucas, Valenzuela Gabriela Reyes, Ibarra Manuel, Guido Paulo Cáceres, Bressan Ignacio, Marin Nora, Delaven Sandra Fabiana, Agostini Silvana, Montilla Carlos Pérez, López María Emilia, Cresta Araceli, Armeno Marisa, Bournissen Facundo García, Caraballo Roberto, Schaiquevich Paula
Unit of Innovative Treatments, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
National Scientific and Technological Research Council, Buenos Aires, Argentina.
Epilepsia. 2025 Apr;66(4):1143-1154. doi: 10.1111/epi.18255. Epub 2025 Jan 13.
Identifying factors influencing cannabidiol (CBD) exposure can optimize treatment efficacy and safety. We aimed to describe the population pharmacokinetics of CBD in children with drug-resistant developmental and epileptic encephalopathies (DEEs) and assess the influence of environmental, pharmacological, and clinical characteristics on CBD systemic exposure.
Data from two pharmacokinetic studies of patients aged 2-18 years with DEEs were included (N = 48 patients). Serial blood samples were collected during maintenance treatment, before and after the morning dose, and up to 6 h after a dose of a purified CBD oil formulation, with or without a normocaloric breakfast. CBD plasma concentrations were also available following administration of a CBD-enriched formulation. Samples were quantified using a validated liquid chromatography/tandem mass spectrometry assay. A CBD population pharmacokinetic model was developed using nonlinear mixed-effects modeling. The effects of formulation, concomitant food intake, and demographic, clinical, and pharmacological factors on CBD pharmacokinetics were evaluated. Simulated maximum plasma concentration (C) and area under the concentration-time curve between 0 and 12 h (AUC) were calculated.
A one-compartment model with transit compartments and first-order elimination best described CBD pharmacokinetics. Mean values for CBD apparent clearance (CL/F) and volume of distribution (V/F) were 143.5 L/h and 1892.4 L, respectively. Weight was allometrically scaled for V/F and CL/F, sex was associated with V/F, and both formulation and food condition were associated with F (relative bioavailability). CBD C increased by 41% and AUC by 45% when CBD was administered with food compared to fasting. Dose-normalized AUC was approximately 50% lower with CBD-enriched oil compared to purified CBD.
In the present study, we described the effects of food and formulation on CBD exposure in children with DEEs. Increased CBD exposure with food intake and significant changes in drug exposure when switching between CBD formulations should be considered in patient management.
确定影响大麻二酚（CBD）暴露的因素可优化治疗效果和安全性。我们旨在描述CBD在耐药性发育性和癫痫性脑病（DEE）儿童中的群体药代动力学，并评估环境、药理学和临床特征对CBD全身暴露的影响。
纳入两项针对2至18岁DEE患者的药代动力学研究数据（N = 48例患者）。在维持治疗期间、晨服剂量前后以及服用纯化CBD油制剂一剂后长达6小时内采集系列血样，无论是否食用等热量早餐。服用富含CBD的制剂后也可获得CBD血浆浓度。使用经过验证的液相色谱/串联质谱分析法对样本进行定量。采用非线性混合效应模型建立CBD群体药代动力学模型。评估制剂、同时摄入食物以及人口统计学、临床和药理学因素对CBD药代动力学的影响。计算模拟的最大血浆浓度（C）和0至12小时浓度-时间曲线下面积（AUC）。
具有转运室和一级消除的单室模型最能描述CBD的药代动力学。CBD表观清除率（CL/F）和分布容积（V/F）的平均值分别为143.5 L/h和1892.4 L。V/F和CL/F按体重进行异速缩放比例，性别与V/F相关，制剂和食物状况均与F（相对生物利用度）相关。与空腹相比，与食物一起服用CBD时，CBD的C增加41%，AUC增加45%。与纯化CBD相比，富含CBD的油剂剂量标准化后的AUC约低50%。
在本研究中，我们描述了食物和制剂对DEE儿童CBD暴露的影响。在患者管理中应考虑食物摄入导致CBD暴露增加以及在CBD制剂之间切换时药物暴露的显著变化。
