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

项目概要/摘要： 评价眼科药物产品在人体中的生物等效性是具有挑战性的伦理和实践 原因通常，动物模型用于评价眼科生物等效性。不幸的是， 将动物模型结果转化为人类已被证明是难以实现的。迫切需要发展 计算工具来协助物种间的翻译。基于生理学的模型外推可以提供 解释药代动力学（PK）和药效学（PD）种间差异的方法。的 拟议工作的目标是开发一个翻译工具框架，用于捕捉种间差异 使用基于生理学的模型外推方法，研究眼用药品的PK和PD。到 为了促进框架开发，我们将收集基于生理学的兔和人眼科PK和PD 从文学的模式。模型组件将与我们现有的模型集成，以创建优化的模型。 我们的团队在多尺度眼科建模方面的经验使该框架能够包括不同的模型。 复杂性（房室，准3D，2D和新型2.5D模型），提供了更完整的图片 潜在的外推解决方案与实现单一模型类型。模型细节（即建模组织， 段、复杂性、生理现象等）将被组织在一个电子表格，其中将包括模型 能力和局限性。与此同时，一个开源数据库比较了兔子和人类的解剖结构， 将创建生理参数值/值范围。收集和优化的兔PK和PD模型 将通过改变解剖学、生理学和生物物理学， 参数值。常见的给药方案（溶液、固体和玻璃体内给药） 悬浮液和乳剂）将使用外推、收集和优化的人眼 PK和PD模型用于比较。模拟结果的比较将能够识别 目前翻译知识的差距。该框架将允许评估关闭这些设施的潜在解决方案。 知识差距。该项目将通过提高监管信心、速度和 提高新的和仿制的眼科药品批准程序的效率，并降低成本， 公众

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.