Lucas Brstilo, Gabriela Reyes Valenzuela, Manuel Ibarra, Paulo Cáceres Guido, Ignacio Bressan, Nora Marin, Sandra Fabiana Delaven, Silvana Agostini, Carlos Pérez Montilla, María Emilia López, Araceli Cresta, Marisa Armeno, Facundo García Bournissen, Roberto Caraballo, Paula Schaiquevich
{"title":"大麻二酚的人群药代动力学以及食物和配方对耐药发育性和癫痫性脑病儿童全身暴露的影响。","authors":"Lucas Brstilo, Gabriela Reyes Valenzuela, Manuel Ibarra, Paulo Cáceres Guido, Ignacio Bressan, Nora Marin, Sandra Fabiana Delaven, Silvana Agostini, Carlos Pérez Montilla, María Emilia López, Araceli Cresta, Marisa Armeno, Facundo García Bournissen, Roberto Caraballo, Paula Schaiquevich","doi":"10.1111/epi.18255","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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<sub>max</sub>) and area under the concentration-time curve between 0 and 12 h (AUC<sub>0-12</sub>) were calculated.</p><p><strong>Results: </strong>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<sub>max</sub> increased by 41% and AUC<sub>0-12</sub> by 45% when CBD was administered with food compared to fasting. Dose-normalized AUC<sub>0-12</sub> was approximately 50% lower with CBD-enriched oil compared to purified CBD.</p><p><strong>Significance: </strong>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.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6000,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Population pharmacokinetics of cannabidiol and the impact of food and formulation on systemic exposure in children with drug-resistant developmental and epileptic encephalopathies.\",\"authors\":\"Lucas Brstilo, Gabriela Reyes Valenzuela, Manuel Ibarra, Paulo Cáceres Guido, Ignacio Bressan, Nora Marin, Sandra Fabiana Delaven, Silvana Agostini, Carlos Pérez Montilla, María Emilia López, Araceli Cresta, Marisa Armeno, Facundo García Bournissen, Roberto Caraballo, Paula Schaiquevich\",\"doi\":\"10.1111/epi.18255\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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<sub>max</sub>) and area under the concentration-time curve between 0 and 12 h (AUC<sub>0-12</sub>) were calculated.</p><p><strong>Results: </strong>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<sub>max</sub> increased by 41% and AUC<sub>0-12</sub> by 45% when CBD was administered with food compared to fasting. Dose-normalized AUC<sub>0-12</sub> was approximately 50% lower with CBD-enriched oil compared to purified CBD.</p><p><strong>Significance: </strong>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.</p>\",\"PeriodicalId\":11768,\"journal\":{\"name\":\"Epilepsia\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":6.6000,\"publicationDate\":\"2025-01-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Epilepsia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/epi.18255\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Epilepsia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/epi.18255","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Population pharmacokinetics of cannabidiol and the impact of food and formulation on systemic exposure in children with drug-resistant developmental and epileptic encephalopathies.
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 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 (Cmax) and area under the concentration-time curve between 0 and 12 h (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 143.5 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 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.
期刊介绍：
Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
