Population pharmacokinetics of cannabidiol and the impact of food and formulation on systemic exposure in children with drug‐resistant developmental and epileptic encephalopathies

Abstract

Objective: 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. Methods: 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 6h 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 (Cmax) and area under the concentration–time curve between 0 and 12h (AUC0-12) were calculated. Results: 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 143.5L/h and 1892.4L, 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 Cmax increased by 41% and AUC0-12 by 45% when CBD was administered with food compared to fasting. Dose-normalized AUC0-12 was approximately 50% lower with CBD-enriched oil compared to purified CBD. Significance: 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.