Natural Product-Drug Interaction Research: The Roadmap to Best Practices

 描述（由申请人提供）：随着天然产物（NP）销售的增加，不良NP-药物相互作用（NPDI）的风险增加，但推定的NPDI的药代动力学（PK）说明和临床相关性仍然难以捉摸。评估NPDI的风险比评估药物相互作用（DDI）更具挑战性，这通常是由于对导致这些相互作用的单个NP成分的PK知识相对较少。拟议的U 54中心将通过一系列精心设计的人体体外和体内研究（称为相互作用项目）为NPDI研究制定路线图，这些研究涉及4-6个对临床相关NPDI构成潜在风险的优先级NP。将为互动项目产生的数据建立一个储存库，并将通过一个公共门户网站向各种目标受众传播结果。该U 54中心由一支经验丰富的研究团队组成，包括具有NPDI专业知识的药代动力学专家，以及NP化学，DDI和健康信息交流方面的专业知识。与指导委员会合作，制定一项将机械方法与实际考虑因素相结合的创新战略（例如，NPs的受欢迎程度）将用于选择和优先考虑4-6个NPs，以便在交互项目中进行进一步研究。机制方面包括来自Informatics Core的广泛使用的药物相互作用数据库（DIDB）的策划临床NDPI数据、结构警报以及令人信服的初步临床和计算机NPDI数据。一旦选定，NP将被输入决策树，以评估NPDI责任和与受害者药物相互作用的可能意义。与此同时，药理学核心将为人体体外和体内研究制定详细的工作说明书，而分析核心将为相互作用项目寻找、获取和表征选定的NP。每个项目完成后，分析中心将分析PK样本，药理学中心将开发基于生理学的PK模型，以进一步评估相互作用项目结果的临床相关性。在这些项目中，Informatics Core将创建一个数据存储库，嵌入一个名为NaPDI应用程序的基于网络的公共门户应用程序中，用于天然产物-药物相互作用应用程序。该存储库使用DIDB框架构建，将允许研究人员访问原始数据和总结结果。U 54中心还将根据互动项目的经验和结果，通过公共门户网站与研究社区开发和分享NPDI研究的最佳实践建议。将通过对目标受众-研究人员/从业人员和普通公众-进行用户体验和品牌内容研究，确保有效传播互动项目的成果，以完善公共门户网站的内容。信息学核心将确保U 54中心的结果得到存档、组织、分析和广泛宣传，从而改进未来NPDI研究的设计，并最终改进临床相关NPDI最佳管理的决策。

 DESCRIPTION (provided by applicant): As natural products (NP) sales increase, the risk of adverse NP-drug interactions (NPDIs) increases, yet the pharmacokinetic (PK) elucidation and clinical relevance of putative NPDIs remain elusive. Assessing the risk of NPDIs is more challenging than that of drug-drug interactions (DDIs), often due to relatively scant PK knowledge of individual NP constituents that perpetrate these interactions. The proposed U54 Center will develop a roadmap for NPDI research through a series of well-designed human in vitro and in vivo studies (termed Interaction Projects) on 4-6 priority NPs that pose a potential risk for clinically relevant NPDIs. A repository will be developed for the data generated from the Interaction Projects, and results will be communicated to various target audiences through a public portal. This U54 Center is composed of an accomplished team of investigators, including pharmacokineticists with expertise in NPDIs, complemented by expertise in NP chemistry, DDIs, and health information communication. In collaboration with the Steering Committee, an innovative strategy that combines a mechanistic approach with practical considerations (e.g., popularity of the NPs) will be used to select and prioritize 4-6 NPs for further investigation in te Interaction Projects. Mechanistic aspects include curated clinical NDPI data from the widely used Drug Interaction Database (DIDB) of the Informatics Core, structural alerts, and compelling preliminary clinical and in silico NPDI data. Once selected, the NPs will be entered into a Decision Tree for assessment of NPDI liability and probable significance of interactions with victim drugs. In parallel, the Pharmacology Core will develop detailed Statements of Work for the human in vitro and in vivo studies - while the Analytical Core will source, acquire, and characterize the selected NPs - for the Interaction Projects. Upon completion of each project, the Analytical Core will analyze the PK samples, and the Pharmacology Core will develop physiologically-based PK models for further assessment of the clinical relevance of the Interaction Project results. Throughout these projects, the Informatics Core will create a data repository embedded within a public portal web-based application named, NaPDI app, for Natural Product-Drug Interaction application. The repository, built using the DIDB framework, will allow researchers to access both raw data and summarized results. The U54 Center will also develop and share Best Practices recommended for the conduct of NPDI studies, based on the experience with and results from the Interaction Projects, with the research communities via the public portal. Effective dissemination of the Interaction Project results will be ensured through user experience and brand content studies with target audiences - researchers/practitioners and lay public - to refine the public portal content. The Informatics Core will ensure that the U54 Center's results are archived, organized, analyzed, and well-publicized, allowing for improved design of future NPDI research and ultimately, improved decisions on the optimal management of clinically relevant NPDIs.