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

项目总结 低成本的仿制药为美国医疗体系节省了约2.2万亿美元 过去十年。因此，仿制药在美国卫生系统的可持续性中发挥着关键作用。仿制药 药品是在充分证明与相应品牌药品相同的基础上批准的。 批准的关键证据是生物等效性(BE)。药代动力学(PK)是最常用的BE 系统作用药物的终点，因为全身暴露在各自作用部位的上游。 然而，基于PK的方法，如果是可测量的，可能不足以证明BE用于局部行动 如果局部和全身暴露之间存在非线性关系，则可能会导致药物中毒。此外，系统性的 可变性可能会对当地药物暴露的回顾评估产生偏差。据我们所知， 系统性和局部性药物暴露之间的一致性或不一致性尚未得到充分解决 在公共领域。 定量方法和模型在新药发现和开发领域得到了广泛的应用 为更高效、更具成本效益的发展计划提供信息。基于生理的药代动力学 (PBPK)建模是定量模型总括的关键工具之一。PBPK模型 是一种有效的工具，可以集成有关产品特征、个体生理的信息 受试者，以及群体内受试者之间的变异性，以模拟整个 在没有进行体内PK研究的情况下，对药物进行胃肠道和随后的全身处置。PBPK模型 在支持仿制药开发和监管决策方面表现出了希望，因为在一项 从模型集成证据的角度来看，它能够利用生成的所有先验知识来支持 对各自名牌药品的监管审批。 我们将生成、分析和集成创新的体外数据和PBPK建模，以评估一致性 针对胃肠道的药物的全身和局部药物暴露之间的水平。集成的新兴模式 证据框架将能够在地方和系统两级进行BE评估。这一点将在考虑到 健康受试者和克罗恩病患者来检验(虚拟)在健康成人中进行研究的假设 可以安全地在目标患者群体中推广。我们有出色的体外测试(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、鲁米那药物 浓度数据集。一旦建立，该框架还可以扩展到集成局部预测 暴露与肠上皮细胞寿命最终预测其药效学效应的时间进程 肠细胞靶向药物通过将嵌套的肠细胞内酶周转模型整合到 SIMCEP™模拟器中的机械式M-ADAM模型。

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.