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

项目摘要/摘要： 评估眼科药物产品在人体内的生物等效性是伦理和实践上的挑战。 理由。通常，动物模型被用来评估眼科生物等效性。不幸的是， 事实证明，将动物模型的结果转化为人类是难以捉摸的。迫切需要发展 协助物种间转换的计算工具。基于生理的模型外推可以提供 一种解释种间药代动力学(PK)和药效学(PD)差异的方法。这个 拟议工作的目标是开发一个用于捕捉物种间差异的翻译工具框架 在眼科药物产品的PK和PD中采用基于生理学的模型外推方法。至 促进框架开发，我们将收集基于生理的兔和人眼科PK和PD 文学作品中的模特。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部建模方面的经验使该框架能够包括各种不同的模型 复杂性(分区、准3D、2D和新的2.5D模型)，这提供了更完整的图景 潜在的外推解决方案与实施单一模型类型的对比。模型细节(即，建模的组织， 细分、复杂性、生理现象等)将组织在电子表格中，其中将包括模型 功能和限制。同时，一个开放源码数据库比较了兔子和人类的解剖和 将创建生理参数值/值范围。兔PK和PD模型的收集和优化 将通过改变解剖学、生理学和生物物理学来推断/放大到人类模型 参数值。常见的给药方案(局部和玻璃体内给药，固体 悬浮液和乳剂)将使用外推、收集和优化的人类眼科 PK和PD模型用于比较目的。模拟结果的比较将使我们能够识别 目前的翻译知识差距。该框架将允许对关闭这些问题的潜在解决方案进行评估 知识鸿沟。该项目将通过提高监管信心、速度和 提高眼科新药和仿制药审批程序的效率，并通过降低 公开的。

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.