Computational Biology (Cobi) Tools as a Framework for Physiologically-Based Pharmacokinetic/Pharmacodynamic Model Extrapolation from Rabbit to Human for Ophthalmic Drug Products

计算生物学 (Cobi) 工具作为基于生理学的药代动力学/药效学模型外推从兔到人眼科药品的框架

• 批准号: 10116143
• 负责人: Carrie German
• 金额: $ 17.99万
• 依托单位: CFD RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116143
• 关键词: Computational; Biology; Cobi; Tools; Framework

Project Summary/Abstract: Evaluating bioequivalence of ophthalmic drug products in humans is challenging for ethical and practical reasons. Often, animal models are used to evaluate ophthalmic bioequivalence. Unfortunately, methods for translation of animal model results to humans has proven elusive. There is a critical need to develop computational tools to assist with interspecies translation. Physiologically-based model extrapolation can provide a means for explaining interspecies differences in pharmacokinetics (PK) and pharmacodynamics (PD). The objective of the proposed work is to develop a translational tool framework for capturing interspecies differences in the PK and PD of ophthalmic drug products using physiologically-based model extrapolation methods. To facilitate framework development, we will collect physiologically-based rabbit and human ophthalmic PK and PD models from literature. Model components will be integrated with our existing models to create optimized models. Our team’s experience in multiscale ophthalmic modeling enables the framework to include models of varying complexity (compartmental, quasi-3D, 2D and novel 2.5D models), which provides are more complete picture of potential extrapolation solutions versus implementing a single model type. Model details (i.e. modeled tissues, segment, complexity, physiological phenomena, etc.) will be organized in a spreadsheet which will include model capabilities and limitations. In parallel, an opensource database comparing rabbit and human anatomical and physiological parameter values/value ranges will be created. Collected and optimized rabbit PK and PD models will be extrapolated/scaled up to human models by changing anatomical, physiological and biophysical parameter values. Common dosing scenarios (topical and intravitreal administration of solutions, solid suspensions and emulsions) will be simulated using extrapolated, collected and optimized human ophthalmic PK and PD models for comparison purposes. Comparison of simulation results will enable identification of the current translational knowledge gaps. The framework will allow evaluation of potential solutions to closing these knowledge gaps. This project will enhance public health by improving regulatory confidence, speed and efficiency in the approval process for new and generic ophthalmic drug products and by decreasing costs to the public.

项目摘要/摘要： 评估眼科药品在人体中的生物等效性在伦理和实践上都具有挑战性 不幸的是，动物模型通常用于评估眼科生物等效性。 事实证明，将动物模型结果转化为人类是难以实现的，因此迫切需要进行开发。 有助于基于生理学的模型外推的计算工具。 一种解释药代动力学 (PK) 和药效学 (PD) 种间差异的方法。 拟议工作的目标是开发一个翻译工具框架来捕捉种间差异 使用基于生理学的模型外推方法进行眼科药品的 PK 和 PD 分析。 促进框架开发，我们将收集基于生理学的兔子和人类眼科 PK 和 PD 文献中的模型组件将与我们现有的模型集成以创建优化的模型。 我们团队在多尺度眼科建模方面的经验使该框架能够包含不同的模型 复杂性（隔室、准 3D、2D 和新颖的 2.5D 模型），提供了更完整的图像 潜在的外推解决方案与实施单一模型类型的比较。模型细节（即建模的组织， 部分、复杂性、生理现象等）将被组织在一个电子表格中，其中包括模型 同时，比较兔子和人体解剖学和局限性的开源数据库。 将创建收集和优化的兔 PK 和 PD 模型的生理参数值/值范围。 将通过改变解剖学、生理学和生物物理来推断/扩大到人体模型 参数值。常见的给药方案（溶液的局部和玻璃体内给药、固体） 悬浮液和乳液）将使用外推、收集和优化的人体眼科进行模拟 用于比较目的的 PK 和 PD 模型可以比较模拟结果。 该框架将允许评估弥补这些差距的潜在解决方案。 该项目将通过提高监管信心、速度和效率来增强公共卫生。 提高新药和非专利眼科药品的审批流程并降低成本 民众。