Development and verification of in vitro integrated mechanistic population-based PBPK model framework towards virtual bioequivalence assessment of locally acting drug products in the GI tract

开发和验证基于体外综合机械群体的 PBPK 模型框架，以对胃肠道中局部作用的药物产品进行虚拟生物等效性评估

• 批准号: 10599428
• 负责人: Rodrigo Cristofoletti
• 金额: $ 30万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599428
• 关键词: Development; verification; vitro; integrated; mechanistic

PROJECT SUMMARY Lower-cost generic drugs generated approximately $2.2 trillion in savings to the US healthcare system in the past decade. Therefore, generic drugs play a pivotal role in the sustainability of the US health system. A generic drug is approved on the basis of sufficient demonstration of sameness to the corresponding brand-name drug. Critical evidence for approval is bioequivalence (BE). Pharmacokinetics (PK) is the most commonly used BE endpoint for systemically acting drugs since systemic exposure is upstream of the respective site of action. However, the PK-based approach, if measurable, may not be sufficient for demonstrating BE for locally acting drugs if there is a non-linear relationship between local and systemic exposures. Furthermore, systemic variability may bias the retrospective assessment of local drug exposure. To the best of our knowledge, concordance or discordance between systemic and local drug exposures has not been adequately addressed in public domain. Quantitative methods and modeling have been widely used in the realm of new drug discovery and development to inform more efficient and cost-effective development programs. Physiologically-based pharmacokinetic (PBPK) modeling is one of the key tools under the overarching umbrella of quantitative models. PBPK models are an effective tool to integrate information about the product characteristics, the physiology of the individual subject, and the variability among subjects within a population to simulate the local bioavailability throughout the GI tract and subsequent systemic disposition of the drug without conducting in vivo PK studies. PBPK models have shown promise in supporting generic drug development and regulatory decision-making, since, under a model-integrated evidence perspective, it enables the leveraging of all prior knowledge generated to support the regulatory approval of the respective brand-name drug product. We will generate, analyze and integrate innovative in vitro data and PBPK modeling to assess the concordance level between systemic and local drug exposures for drugs targeting the GI tract. The emerging model integrated evidence framework will enable BE assessment at local and systemic levels. This will be done considering healthy subjects and Crohn’s disease patients to test the hypothesis that (virtual) BE studies in healthy adults can be safely generalized across target patient populations. We have excellent in vitro testing (and model-based data analysis, i.e. SIVA toolkit) and PBPK modeling capabilities, along with unique replicate BE, PK, luminal drug concentration data sets. Once established, this framework can also be extended to integrate prediction of local exposure and intestinal epithelium life span to ultimately predict the time course of pharmacodynamic effects of enterocyte-targeting drugs by integrating the nested enzyme-within-enterocyte turnover model into the mechanistic M-ADAM model in the Simcyp™ simulator.

项目概要 低成本仿制药为美国医疗保健系统节省了约 2.2 万亿美元 因此，仿制药在美国卫生系统的可持续发展中发挥着关键作用。 药物的批准是基于充分证明与相应品牌药物的相同性。 批准的关键证据是生物等效性 (BE) 是最常用的 BE。 全身作用药物的终点，因为全身暴露位于各自作用位点的上游。 然而，基于 PK 的方法（如果可测量）可能不足以证明局部作用的 BE 局部和全身暴露之间是否存在非线性药物关系。 据我们所知，变异性可能会使局部药物暴露的回顾性评估产生偏差。 全身和局部药物暴露之间的一致性或不一致尚未得到充分解决 在公共领域。 定量方法和建模已广泛应用于新药发现和开发领域 为更有效和更具成本效益的开发计划提供信息。 (PBPK) 建模是 PBPK 模型总体框架下的关键工具之一。 是整合有关产品特性、个人生理信息的有效工具 受试者，以及群体内受试者之间的变异性，以模拟整个过程中的局部生物利用度 胃肠道和随后的药物全身处置，无需进行体内 PBPK 模型。 在支持仿制药开发和监管决策方面表现出了承诺，因为 模型集成的证据视角，它能够利用生成的所有先验知识来支持 相应品牌药品的监管批准。 我们将生成、分析和整合创新的体外数据和 PBPK 模型来评估一致性 针对胃肠道的药物的全身和局部药物暴露之间的水平。 证据框架将使地方和系统层面的BE评估成为可能，这将在考虑到的情况下进行。 健康受试者和克罗恩病患者测试健康成人（虚拟）BE 研究的假设 可以安全地推广到目标患者群体。我们拥有出色的体外测试（和基于模型的测试）。 数据分析（即 SIVA 工具包）和 PBPK 建模功能，以及独特的复制 BE、PK、luminal 药物 一旦建立，该框架还可以扩展以整合当地的预测。 暴露和肠上皮寿命，最终预测药效作用的时间过程 通过将巢式肠细胞内酶周转模型整合到肠细胞靶向药物中 Simcyp™ 模拟器中的机械 M-ADAM 模型。