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

项目总结/摘要 基于生理学的药代动力学（PBPK）建模已成为药物代谢的重要组成部分。 新药和仿制药的药物开发过程。对于后者， USFDA支持使用建模和模拟来建立（虚拟）生物等效性 参比品和供试品之间的差异。结合PBPK建模可以增加 对体外数据的信心，并有助于减少或消除对临床试验的需求，从而 加快批准负担得起的药品。这项资助计划的首要目标是 是通过增强MPML MechDermA， 模型，定义体外数据使用的最佳实践，分析和重新考虑研究 用于生成数据的协议。目标1是整理和提供一个 可用于验证和/或优化PBPK的皮肤渗透性数据的广泛数据库 模型该数据库还将用于Aim 2，以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。 描述药物分配、扩散和结合的MPML MechDermA将 系统评价，从而确定最佳性能组合， QSAR。如有必要，将开发新的定量构效关系，以改进从头算预测。的 将增强经验证的IVPT模块，以告知IVPT研究的设计，包括 受体溶液溶解度和LLOQ要求的估计。在目标3下，a 将进行一系列全面的体外表征、释放和渗透研究， 进行，重点是氢化可的松（HC）和丙酸氯倍他索的四种制剂 （CP）。这些数据将用于目标4，以开发稳健的PBPK模型， 外推到体内情况，其中将利用已识别的文献数据来验证 健康和患病人群的体内模型。在目标5下，内部人道主义协调和国家方案 将设计和表征具有改良制剂属性的药品。这些 修改后的配方将用于挑战PBPK模型，这将验证模型的 区分生物等效性的能力。作为这一目标的一部分，现有的配方模型将 增强和先进的释放技术，如微球模型， 将研究脂质体。目标6涉及同时使用的赋形剂/渗透促进剂 吸收，特别关注丙二醇。丙二醇的实验数据 丙酸氯倍他索乳膏的渗透性（目的2）将用于研究同时 吸收，并使用MPML MechDermA中的赋形剂模型对此进行解释。

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.