Progressing integration of in vitro topical formulation characterisation, release and permeation data to the next level - PBPK based extrapolation to bioequivalence assessment in virtual populations

将体外局部制剂表征、释放和渗透数据整合到一个新的水平——基于 PBPK 的虚拟群体生物等效性评估的外推法

• 批准号: 10356642
• 负责人: Sebastian Polak
• 金额: $ 24.99万
• 依托单位: CERTARA UK LIMITED
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356642
• 关键词: Progressing; integration; vitro; topical; formulation

Project Summary/ Abstract Physiologically Based Pharmacokinetic (PBPK) modelling has become an important part of the drug development process, both for novel and generic drug products. For the later, the USFDA supports the use of modelling and simulation for establishing (virtual) bioequivalence between reference and test products. Incorporation of PBPK modelling can increase confidence in in vitro data and help to reduce or eliminate the need for clinical trials, thus accelerating approval of affordable drug products. The overarching aim of this grant proposal is to progress integration of in vitro data to PBPK models by enhancing the MPML MechDermA model, defining best practices for in vitro data usage, and analysing and re-considering study protocols utilised to generate the data. Aim 1 is to collate and make publically available an extensive database of skin permeability data that can be used to verify and/or optimize PBPK models. This database will also be used in Aim 2 to verify and optimize simulations of different IVPT setups, such as different membrane types, diffusion cell types, etc. The QSARs built in to the MPML MechDermA describing drug partitioning, diffusion and binding will be systematically evaluated, resulting in identification of the best performing combination of QSARs. If necessary new QSARs will be developed to improve ab initio predictions. The verified IVPT module will be enhanced to inform the design of IVPT studies including estimation of receptor solution solubility and LLOQ requirements. Under Aim 3, a comprehensive series of in vitro characterization, release and permeation studies will be conducted, focusing on four formulations of hydrocortisone (HC) and clobetasol propionate (CP). This data will be used in Aim 4 to develop robust PBPK models and subsequently extrapolate to the in vivo scenario, where identified literature data will be leveraged to verify the in vivo models for healthy and diseased populations. Under Aim 5, in-house HC and CP drug products with a modified formulation attribute will be designed and characterized. These modified formulations will be used to challenge the PBPK models, which will verify the Model’s ability to distinguish bio(in)equivalence. As part of this Aim, existing formulation models will be enhanced and models for advanced release technologies such as microspheres and liposomes will be investigated. Aim 6 deals with concurrent excipient/penetration enhancer absorption with a particular focus on propylene glycol. Experimental data on propylene glycol penetration from the clobetasol propionate cream (Aim 2), will be used to study concurrent absorption and account for this using the excipient model in the MPML MechDermA.

项目概要/摘要 基于生理学的药代动力学（PBPK）建模已成为重要组成部分 药物开发过程，无论是新药还是仿制药。 美国 FDA 支持使用建模和模拟来建立（虚拟）生物等效性 结合 PBPK 模型可以增加参考产品和测试产品之间的差异。 对体外数据的信心，有助于减少或消除临床试验的需要，从而 加速批准负担得起的药品。 是通过增强 MPML MechDermA 将体外数据集成到 PBPK 模型中 模型，定义体外数据使用的最佳实践，以及分析和重新考虑研究 用于生成数据的协议目标 1 是整理并公开可用的数据。 广泛的皮肤渗透性数据数据库，可用于验证和/或优化 PBPK 该数据库还将在 Aim 2 中用于验证和优化不同的模拟。 IVPT 设置，例如不同的膜类型、扩散池类型等。内置的 QSAR 描述药物分配、扩散和结合的 MPML MechDermA 将是 进行系统评估，从而确定性能最佳的组合 如有必要，将开发新的 QSAR 以改进从头开始的预测。 经过验证的 IVPT 模块将得到增强，为 IVPT 研究的设计提供信息，包括 估计受体溶液溶解度和 LLOQ 要求。在目标 3 下，a 一系列全面的体外表征、释放和渗透研究将 进行，重点关注氢化可的松 (HC) 和丙酸氯倍他索的四种配方 (CP)。该数据将用于目标 4 以及随后的开发稳健的 PBPK 模型。 推断到体内场景，其中将利用已识别的文献数据来验证 目标 5 下的健康和患病人群的体内模型，内部 HC 和 CP。 将设计和表征具有修改的配方属性的药品。 修改后的配方将用于挑战 PBPK 模型，这将验证模型的 作为该目标的一部分，现有的制剂模型将具有区分生物等效性的能力。 先进释放技术的增强和模型，例如微球和 将研究脂质体，目标 6 涉及同时使用的赋形剂/渗透促进剂。 特别关注丙二醇的吸收实验数据。 丙酸氯倍他索乳膏的渗透（目标 2），将用于研究并发 吸收并使用 MPML MechDermA 中的赋形剂模型对此进行解释。