Tissue pharmacology imaging and modeling

组织药理学成像和建模

• 批准号: 8768697
• 负责人: Namandje N Bumpus
• 金额: $ 53.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768697
• 关键词: Adherence; Animals; Biological; Biophysics; Cells; Clinical; Clinical Research; Colon; Colorectal; Computer Simulation; Computing Methodologies; Contraceptive Agents; Coupled; Critical Pathways; Data; Development; Diphosphates; Dosage Forms; Dose; Drug Delivery Systems; Drug Kinetics; Drug Packaging; Drug Transport; Elements; Environment; Evaluation; Fostering; Goals; HIV; Human; Image; In Vitro; Infection; Intervention; Knowledge; Link; Liquid substance; Local Microbicides; Location; Measurement; Measures; Methodology; Methods; Mission; Modeling; Mucous Membrane; Nucleotides; Optical Coherence Tomography; Outcome; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Physiology; Process; Prodrugs; Prophylactic treatment; Raman Spectrum Analysis; Regimen; Research Design; Resistance; Resolution; Sampling Studies; Science; Site; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrum Analysis; Structure; Tenofovir; Therapeutic; Time; Tissue Model; Tissue Sample; Tissues; Translating; Vagina; Viral; animal data; base; design; drug efficacy; enema administration; improved; in vivo; instrument; microbicide; model development; nonhuman primate; pharmacokinetic model; pre-clinical; product development; programs; prophylactic; prototype; rectal; rectal microbicide; research and development; time interval; transmission process; vaginal microbicide

PROJECT 3 (TISSUE MODELING PROJECT) - PROJECT SUMMARY A successful microbicide product has pharmacokinetics (PK) that effect prophylactic pharmacodynamics (PD). Product design should manipulate candidate compositions, volumes, and drug packaging in a rational manner to yield target PK/PD; but we have limited understanding of this relationship. Further, our methods for experimentally evaluating PK in animals and humans are limited: they do not delineate drug concentration distributions throughout target compartments where the drugs act, and may miss drug partitioning and concentration gradients that drive drug transport; they fail to measure key molecules, e.g. drug metabolites, HIV, and intracellular molecules that might modulate drug efficacy (e.g. endogenous nucleotides). Thus, drug concentrations in contemporary PK studies, while useful, do not adequately inform us about product PK and may not accurately reflect true prophylactic potential. Project 3 will develop and apply new methodology - experimental and computational - to understand and predict these critical, heretofore missing elements of PK, for the enema microbicide product, as it is being designed and evaluated by the DREAM Program. Our team has synergistic expertise in both experimental methods and computational modeling of the kind needed here. Aims 1 and 3 develop this unprecedented, transformative methodology. Aim 1 integrates detailed MALDI measurements of drug, metabolite and other key molecules in colorectal tissue specimens with those by a specialized instrument that applies confocal Raman spectroscopy - to measure local microbicide drug concentrations in tissue specimens in 3D - coupled to spectral domain optical coherence tomography - to link drug concentration to structures of the mucosal tissue within which drug is migrating. Aim 3 creates a new biophysics and physiology based computational compartmental model of detailed PK for enema designs. It predicts the 3D, time-dependent drug concentration distributions in these compartments - delineating PK with greater resolution than previously possible. Aims 2 and 4 and apply the methods of Aims 1 and 3 to the human studies in Project 1 and 4 and NHP studies in Project 2, helping interpret PK and PD data, and thence understand, design and choose the best microbicide enema designs.

项目 3（组织建模项目）- 项目摘要 成功的杀菌剂产品的药代动力学 (PK) 会影响预防药效 (PD)。 产品设计应以合理的方式操纵候选成分、体积和药物包装 产生目标 PK/PD；但我们对这种关系的了解有限。此外，我们的方法 实验评估动物和人类的 PK 是有限的：它们不能描述药物浓度 分布在药物作用的整个目标区室中，并且可能会错过药物分区和 驱动药物转运的浓度梯度；他们无法测量关键分子，例如药物代谢物， HIV 和可能调节药物功效的细胞内分子（例如内源核苷酸）。由此可见，药 当代 PK 研究中的重点虽然有用，但并没有充分告知我们产品 PK 和 可能无法准确反映真正的预防潜力。项目 3 将开发并应用新的方法 - 实验和计算 - 理解和预测这些关键的、迄今为止缺失的 PK 元素， 灌肠杀菌剂产品，因为它正在由 DREAM 计划设计和评估。我们的团队 拥有此处所需的实验方法和计算建模方面的协同专业知识。 目标 1 和 3 开发了这种前所未有的变革性方法。目标 1 集成了详细的 MALDI 结直肠组织样本中药物、代谢物和其他关键分子的测量 应用共焦拉曼光谱的专用仪器 - 测量局部杀菌剂药物 3D 组织样本中的浓度 - 耦合到谱域光学相干断层扫描 - 进行链接 药物在其中迁移的粘膜组织结构中的浓度。目标 3 创建一个新的 基于生物物理学和生理学的灌肠设计详细 PK 计算隔室模型。它 预测这些区室中的 3D、时间依赖性药物浓度分布 - 描述 PK 比以前更高的分辨率。目标 2 和 4 并将目标 1 和 3 的方法应用于人类 项目 1 和 4 中的研究以及项目 2 中的 NHP 研究，帮助解释 PK 和 PD 数据，然后 了解、设计和选择最佳的杀菌剂灌肠设计。