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.

项目摘要/摘要 基于生理的药代动力学（PBPK）建模已成为重要组成部分 用于新型和通用药品的药物开发过程。稍后， USFDA支持使用建模和仿真来建立（虚拟）生物等效 在参考和测试产品之间。 PBPK建模的合并可以增加 对体外数据有信心，并有助于减少或消除对临床试验的需求，从而 加速批准负担得起的药品。该赠款提案的总体目的 是通过增强MPML机场来促进体外数据与PBPK模型的集成 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 可用于验证和/或优化PBPK的大量皮肤通透性数据数据库 型号。该数据库也将用于AIM 2中，以验证和优化不同的模拟 IVPT设置，例如不同的膜类型，差异类型等。 描述药物分配，扩散和结合的MPML机甲将是 系统评估，从而确定了最佳性能的组合 QSARS。如有必要，将开发新的QSAR，以改善从头算的预测。这 经过验证的IVPT模块将得到增强，以告知IVPT研究的设计 估计受体解决方案解决方案和LLOQ要求。在AIM 3下， 全面的体外表征，释放和渗透研究将是 进行，重点是四个氢化可的松（HC）和丙酸氯苯二酚的公式 （CP）。该数据将用于AIM 4来开发强大的PBPK模型，然后 推断到体内场景，在该方案中，将利用已确定的文献数据来验证 健康和疾病人群的体内模型。在AIM 5，内部HC和CP下 具有改良配方属性的药物将设计和表征。这些 修改的公式将用于挑战PBPK模型，该模型将验证该模型的 能够区分生物（IN）等价的能力。作为此目标的一部分，现有公式模型将是 增强和模型的高级释放技术，例如微球和 将研究脂质体。 AIM 6处理并发赋形剂/渗透增强剂 抽象，特别关注丙二醇。丙二醇的实验数据 丙酸丙酸酯奶油的渗透（AIM 2）将用于研究并发 使用MPML机发中的赋形剂模型进行抽象和解释。