Pharmacology Core

药理学核心项目总结 植物和其他天然产品(NP)的销量继续呈指数级增长，这加剧了人们对 NPs与相应的处方药之间的不良反应。在前四年多的时间里 我们的天然产物药物相互作用研究卓越中心(NaPDI中心)，药理学 CORE为选择、确定优先次序和评价作为沉淀物的高影响核动力源建立了一个框架 潜在的具有临床意义的药代动力学NP-药物相互作用(NPDI)可能导致次优 治疗效果。我们采用了一种严谨、系统的“预测、学习和确认”方法，其中包括Robust 与人体相关的体外系统，药代动力学建模和模拟，以及临床评估 NPDIs的临床相关性。这份续订申请的药理学核心部分提出了三项建议 具体目标是完善和推广在最初筹资期间制定的“最佳做法”。目标1： 药理学核心，与分析核心、信息学核心、管理核心和 指导委员会，将挑选三到五种广泛使用的NPs作为潜在的临床沉淀剂并进行优先排序 使用我们已建立的称为支点模型的方法的重大NPDI。根据我们迄今的经验，我们 我扩展了这一创新模式，以包括快速通道选项，以适应新兴的NP NPDI风险增加，无法对公共卫生需求作出反应。现建议下列优先次序较高的核电项目： KrATOM，大麻产品，肉桂，黑胡椒补充剂，以及组合产品紫锥菊 紫花菊/黄花海豹。目标2：药理学核心将评估这些NPs使用NPDI的易感性 建立了药物代谢酶和转运蛋白活性的体外人体系统，并建立了体外药物代谢系统。 食品和药物管理局推荐的活体外推方法。目标3：药理学 CORE将评估健康志愿者的临床NPDI风险，其中将包括更脆弱的老年人 人口。针对后一类人群的理由是，特定的NPs越来越多地面向老年人 人群中，通常声称副作用比处方药少。药理核心的临床应用 研究能力是NaPDI中心的基石，在此期间完成了五项临床研究 最初的资助期。在整个拟议的项目中，从配套R21赠款中产生的NPP将是 应用于我们的扩展支点模型，并有可能进入我们的NP列表。我们将不断整合新的 临床研究方法，如评估肠道微生物区系的效果和纳入转运蛋白 探索药物代谢酶和转运蛋白的鸡尾酒和生物标记物。药理学核心，in 与NAPDI中心其他核心的协同作用，有效和明确地为 NPDI研究。利用我们世界级团队的势头，我们有信心继续保持下去 通过创新NPDI研究的其他推荐方法和确定临床新方法的发展轨迹 相关的NPDI。

PROJECT SUMMARY OF THE PHARMACOLOGY CORE Sales of botanical and other natural products (NPs) continue to rise exponentially, increasing concerns for adverse interactions between NPs and concomitant prescription medications. During the first four-plus years of our Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), the Pharmacology Core established a framework for the selection, prioritization, and evaluation of high impact NPs as precipitants of potential clinically significant pharmacokinetic NP-drug interactions (NPDIs) that could lead to suboptimal therapeutic outcomes. We adopted a rigorous, systematic ‘predict, learn, and confirm’ approach involving robust human-relevant in vitro systems, pharmacokinetic modeling and simulation, and clinical evaluation to assess the clinical relevance of NPDIs. The Pharmacology Core component of this renewal application proposes three SPECIFIC AIMS that refine and extend the ‘best practices’ developed during the initial funding period. AIM 1: the Pharmacology Core, in collaboration with the Analytical Core, Informatics Core, Administrative Core, and Steering Committee, will select and prioritize three to five widely used NPs as precipitants of potential clinically significant NPDIs using our established method termed the fulcrum model. Based on our experience to date, we have expanded this innovative model to include a fast track option that accommodates emerging NPs with heightened NPDI risk to remain responsive to public health needs. The following high priority NPs are proposed: kratom, hemp products, cinnamon, black pepper supplement, and the combination product Echinacea purpurea/goldenseal. AIM 2: the Pharmacology Core will evaluate the NPDI liability of these NPs using established human in vitro systems for both drug metabolizing enzyme and transporter activity and in vitro to in vivo extrapolation approaches recommended by the Food and Drug Administration. AIM 3: the Pharmacology Core will evaluate the clinical NPDI risk in healthy volunteers that will include a more vulnerable, elderly population. The rationale for targeting the latter group is that specific NPs are increasingly marketed to the aging population, often claiming fewer side effects than prescription medications. The Pharmacology Core’s clinical research capabilities are a cornerstone of the NaPDI Center, having completed five clinical studies during the initial funding period. Throughout the proposed project, NPs that emerge from companion R21 grants will be applied to our expanded fulcrum model and potentially advanced to our NP list. We will continually integrate new clinical research methods, such as evaluating the effects of the gut microbiota and incorporating transporter probe cocktails and biomarkers of drug metabolizing enzymes and transporters. The Pharmacology Core, in synergy with the other Cores of the NaPDI Center, has efficiently and definitively established a new standard for NPDI research. Capitalizing on the momentum of our world class team, we are confident to continue this trajectory by innovating additional recommended approaches for NPDI research and identifying novel clinically relevant NPDIs.