A State-of-the-Art Virtual Bioequivalence Platform and Case Studies on Complex Formulations, Systemic and Local Concentration-based Bioequivalence

项目摘要/摘要 在生物制药领域，虚拟生物等效性(VBE)试验模拟有可能 加快药物开发速度，降低成本，减少人体志愿者暴露 和病人接受不必要的治疗。VBE的基础是已被证明的机械能力 基于生理的药代动力学(PBPK)模型用于模拟真实的患者虚拟队列 它可以取代完整的临床试验。但是，定义良好且经过验证的工作流程和 VBE应用程序尚未完全建立。在无缝的用户中拥有定义良好的工作流- 经过多个案例研究测试的友好、可广泛访问的建模平台将确保 行业和监管机构更广泛地采用VBE。本项目建议开发一种 集成的VBE平台，可针对与健康和 患者的安全性，以及他们最佳和具有成本效益的治疗。能够集成不同的 数据流(关于药物和配方的体外信息、关于什么的生理知识 药物到达作用部位的能力、可变性、生理学和新陈代谢的条件 跨患者)不只是一项软件生产练习，还需要对每个领域有深入的了解 以及该领域的专业知识。这需要得到严格的统计分析的补充，如应用 到真实的临床数据，VBE模拟。我们的总体目标是 ·开发软件平台，支持灵活、适合用途的VBE工作流 利用现有工具和添加自定义模块。 ·提供有关VBE工作流程设计的指导(如何解决特定问题、避免陷阱、 帮助为监管机构/行业设计支持性实验和试验)。 ·最大限度地利用现有体外数据分析和建模工具的能力 提取与所选路线配方差异相关的关键参数值 给药(例如，口服、肌肉注射)。 ·开展六个深入的VBE案例研究，非常贴近现实生活案例，其中应个性化 团队可通过文献报告或内部调查获得临床数据； 体外实验数据已经可用，或将按要求生成。 ·创建自动默认报告模板，清楚地记录工作流程及其 结果，非用户出于评估目的很容易理解(可灵活地 在需要时修改默认模板)。 我们的具体目标分为工作流设计、软件实施和案例研究。我们 预期拟议的研究将导致更广泛的以患者为中心的人群应用 在仿制药开发和监管审查中的PBPK模型，但也用于创新者的药物， 提高世界所有人口的药物效力、可获得性和安全性。

Project Summary/ Abstract In the field of biopharmaceutics, virtual bioequivalence (VBE) trial simulations have the potential to increase the speed of drug development, lower its cost and reduce exposure of human volunteers and patients to unneeded therapies. VBE is based on the proven ability of mechanistic physiologically-based pharmacokinetic (PBPK) models to simulate realistic virtual cohorts of patients which can replace full clinical trials. However, well-defined and verified workflows and examples of VBE applications are not yet fully established. Having well-defined workflows in a seamless, user- friendly, and widely accessible modeling platform tested with multiple case studies will ensure a wider adoption VBE by industry and regulatory bodies. This project proposes to develop an integrated VBE platform yielding optimal decisions for a matter directly related to the health and safety of patients, and their optimal and cost-effective treatment. The capacity to integrate various streams of data (in vitro information on drug and formulations, physiological knowledge of what conditions the ability of a drug to reach its site of action, variability physiology and metabolism across patients) is not just a software production exercise but requires deep knowledge of each area and expertise in the field. This needs to be complemented by rigorous statistical analyses, as applied to real clinical data, of the VBE simulations. Our overall objectives are to • Develop a software platform allowing for flexible, fit-for-purpose, VBE workflows taking advantage of existing tools and adding user-defined modules. • Provide guidance on VBE workflow design (how to solve particular questions, pitfalls to avoid, help with the design of supporting experiments and trials) for regulatory agencies/industries. • Make maximum use of the capabilities of existing in vitro data analysis and modeling tools to extract key parameters values relevant to formulation differences for selected routes of administration (e.g., oral, intra-muscular injection). • Conduct six in-depth VBE case studies, very close to real life cases, where individualized BE clinical data are available to the team through literature reports or internal investigations; Experimental in vitro data is already available or will be generated as required. • Create automated default reporting templates that clearly document the workflow and its results and are easily understood by non-users for assessment purpose (with flexibility to modify default templates when needed). Our specific aims are divided in workflow design, software implementation and case studies. We anticipate that the proposed research will result in a wider patient centric application of population PBPK models in generic drug development and regulatory reviews, but also for innovators’ drugs, enhancing drug efficacy, availability and safety for all the world’s population.