Development and Validation of a PBPK/PD Modeling Strategy for Ophthalmic Drug Products to Support Translation from Preclinical Species to Human

从动物到人类的眼部PBPK/PD模型外推-摘要 仿制药办公室（OGD）的任务之一是审查申办者的申请， 声称与同一药物的获批制剂具有生物等效性的眼用剂型。 申办者公司希望对他们提交的局部作用剂量申请具有高度信心 被认为具有生物等效性（BE）的形式将获得好评。软件体现了 基于生理学的药代动力学（PBPK）/药效学（PD）建模可以作为有用的 替代传统的BE方法，以评估新的局部作用制剂 将在目标患者人群中与获批剂型相比具有BE。 开发最先进的眼部PBPK/PD软件功能，并定义 模型的物种间翻译需要广泛的知识基础， 基金会有才华的科学家应用知识库开发有用的方程和逻辑 适用于软件，高级计算机编程技能，将方程和逻辑编码为用户- 友好的软件，以及其他经验丰富的科学家来测试，验证，记录和支持软件， 没有参与其开发的其他人所期望的应用。 本项目的目标是开发和验证眼用药物的PBPK/PD建模策略 支持从临床前物种到人类的翻译。这将通过一个 结合详尽的综述，扩展临床前和临床PK/PD数据的知识库 眼科产品的成套和遗留模型，开发临床前的机械PBPK/PD模型 在GastroPlus®内的眼隔室吸收和转运™（OCAT™）模型中的种属 软件程序和外推到人类PBPK/PD模型，并验证和记录 所产生的软件供他人使用。通过将分析建立在成熟且经过验证的OCAT™之上， 该模型以前由FDA资助，用于制药和仿制药 今天的制药公司，我们将能够将项目资源完全集中在确定知识差距上， 和新的战略，以支持跨物种翻译的眼部药物输送和建立科学的 以及支持创新开发和执行生物等效性的监管标准 评估，而不是为核心程序及其许多支持开发新代码 能力（例如，积分、绘图、参数敏感性分析、虚拟BE试验模拟）。 在整个过程中，我们将与FDA项目经理和财团保持密切联系 我们建议与我们的合作伙伴以及 FDA应确保团队专注于数据汇编和模型开发活动， 成功完成项目范围内的具体目标。

Ocular PBPK/PD Model Extrapolation from Animal to Human – Abstract The Office of Generic Drugs (OGD) is tasked, among other things, with reviewing sponsor applications for ocular dosage forms that purport to be bioequivalent to the approved formulations for the same drug. Sponsor companies want to have high confidence that applications they submit for locally acting dosage forms thought to be bioequivalent (BE) will receive favorable reviews. Software that embodies physiologically-based pharmacokinetics (PBPK) / pharmacodynamics (PD) modeling can serve as a useful alternative to conventional BE approaches to evaluate the likelihood that a new locally acting formulation will be BE to an approved dosage form in the target patient population. Developing a state-of-the-art capability for ocular PBPK/PD software and defining strategies for interspecies translation of models requires an extensive knowledge base to serve as the scientific foundation. Talented scientists apply the knowledge base in the development of useful equations and logic suitable for software, high-level computer programming skills to encode the equations and logic into user- friendly software, and other experienced scientists to test, validate, document, and support the software for the desired application by others not involved in its development. The goal of this project is to develop and validate a PBPK/PD modeling strategy for ophthalmic drug products to support translation from preclinical species to human. This will be achieved through a combination of an exhaustive review expanding the knowledge base of preclinical and clinical PK/PD data sets and legacy models for ophthalmic products, developing mechanistic PBPK/PD models in preclinical species in the Ocular Compartmental Absorption and Transit™ (OCAT™) model within the GastroPlus® software program and extrapolating to human PBPK/PD models, and validating and documenting the resulting software for use by others. By basing the analyses on the well-established and validated OCAT™ model, which has been funded previously by the FDA and is utilized by both pharmaceutical and generic drug companies today, we will be able to focus project resources entirely on identifying knowledge gaps and new strategies to support interspecies translation for ocular drug delivery and establishing scientific and regulatory standards for supporting innovative development and performing bioequivalence assessments, rather than having to develop new code for the core program and its many support capabilities (e.g., integration, plotting, Parameter Sensitivity Analysis, Virtual BE Trial Simulations). Throughout the effort, we will maintain close contact with the FDA program manager and the Consortium for Ocular PBPK/PD Model Extrapolation that we propose to form with our collaboration partners and the FDA to ensure the team focuses on data compilation and model development activities that will result in successful completion of the specific aims within the scope of the project.