Development and validation of a best practices framework for PBPK analysis for biopharmaceutic applications in support of model-informed biowaivers of fed state BE studies for BCS class II drugs

开发和验证生物制药应用 PBPK 分析的最佳实践框架，以支持 BCS II 类药物的联邦州 BE 研究的模型知情生物豁免

• 批准号: 10454243
• 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: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454243
• 关键词: Development; validation; best; practices; framework

PROJECT SUMMARY Lower-cost generic drugs generated $313 billion in savings to the US healthcare system in 2019 and approximately $2.2 trillion 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). Even though well established, pharmacokinetic-based BE studies are both costly and lengthy. In the case of orally administered drug products, co-administration with food may influence oral absorption, thus BE should be demonstrated under both fasting and fed conditions if the reference listed drug labeling states the product can be taken with or without meals. This requirement poses an additional financial burden on generic manufacturers, which will ultimately be passed along to patients. Furthermore, the regulatory requirement of two in vivo BE studies slows down the generic drug product development process and may increase review cycles and attrition rates due to variability that is related to the drug itself rather than the formulation. 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 absorption 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 develop a best practices framework for integrating drug and drug product data together with gastrointestinal physiology in PBPK models tailored to oral drug administration to predict food-formulation interactions and promote biowaivers of fed state BE studies for poorly soluble and highly permeable drugs. This will be done at both the individual and population levels. We have excellent in vitro testing and PBPK modeling capabilities, along with unique PK and luminal drug concentration data sets. Once established, this framework can also be applied to address emerging issues in generic drug development and assessment, such as BE study protocol changes necessitated, for example, by pandemic situations and hypochlorhydria-formulation interactions.

项目摘要 低成本仿制药在2019年为美国医疗保健系统节省了3130亿美元 在过去的十年中，约有2.2万亿美元。因此，仿制药在可持续性中起关键作用 美国卫生系统。批准仿制药的批准是根据与 相应的品牌药物。批准的关键证据是生物等效性（BE）。即使很好 建立的基于药代动力学的BE研究既昂贵又冗长。在口头管理的情况下 药品，与食物共同给药可能会影响口服吸收，因此应在 禁食和美联储条件，如果参考列出的药物标签指出，则可以使用或不用 餐。该要求对通用制造商造成了额外的财务负担，最终将是 传递给患者。此外，两个体内研究的调节要求减慢了 通用药物产品开发过程，可能会增加审查周期和流失率 这与药物本身有关，而不是配方。 定量方法和建模已被广泛用于新药发现和开发领域 为更有效，更具成本效益的开发计划提供信息。基于生理的药代动力学 （PBPK）建模是定量模型总体保护伞下的关键工具之一。 PBPK型号 是整合有关产品特征的信息，个人生理学的有效工具 受试者以及人群中受试者之间的可变性，以模拟吸收和随后的吸收 无需进行体内PK研究而无需进行药物的全身性处理。 PBPK模型在 支持通用药物开发和监管决策，因为在模型融合的证据下 观点，它可以利用生成的所有先验知识来支持监管部门的批准 各自的名牌药品。 我们将开发一个最佳实践框架，以将药物和药物数据与 针对口服药物给药的PBPK模型中的胃肠道生理学，以预测食品形成 相互作用并促进美联储国家的生物生物，是可溶性和高度渗透性药物的研究。这 将在个人和人口水平上完成。我们有出色的体外测试和PBPK建模 功能，以及独特的PK和Luminal药物浓度数据集。建立后，这个框架 也可以应用于解决通用药物开发和评估中的新兴问题，例如研究 规程变化例如，通过大流行状况和次氯氢化植物形成所必需 互动。