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 成功的微生物剂具有影响预防药效学（PD）的药代动力学（PK）。 产品设计应以合理的方式操纵候选候选作品，体积和药品包装 产生目标PK/PD；但是我们对这种关系的理解有限。此外，我们的方法 实验评估动物和人类的PK是有限的：它们不描述药物浓度 整个毒品法案的目标隔室的分布，可能会错过药物分配和 驱动药物运输的浓度梯度；他们无法测量关键分子，例如药物代谢物， HIV和细胞内分子可能调节药物疗效（例如内源性核苷酸）。因此，药物 当代PK研究的集中虽然有用，但并未充分告知我们产品PK和 可能无法准确反映出真正的预防潜力。项目3将开发并采用新方法 - 实验和计算 - 了解和预测PK的这些关键，迄今为止缺失的元素， 对于灌肠微生物剂产品，它是由Dream计划设计和评估的。我们的团队 在实验方法和计算建模方面都具有协同的专业知识。 目标1和3发展了这种前所未有的变革方法。 AIM 1整合详细的Maldi 与a的药物，代谢产物和其他关键分子的测量 适用共焦拉曼光谱法的专用仪器 - 测量局部杀菌剂药物 3D的组织样品的浓度 - 耦合到光谱域光学相干断层扫描 - 连接 药物浓度到药物迁移的粘膜组织的结构。 AIM 3创建了一个新的 基于生物物理学和生理学基于灌肠设计的详细PK的计算隔室模型。它 预测这些隔室中的3D，时间依赖性药物浓度分布 - 用 分辨率比以前更大。目标2和4，并将目标1和3的方法应用于人类 项目1和项目2中的NHP研究中的研究有助于解释PK和PD数据，从而有助于解释 了解，设计并选择最佳的杀菌剂灌肠设计。