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

项目摘要/摘要 基于生理的药代动力学(PBPK)建模已成为 新药和仿制药产品的药物开发过程。对于后者， 美国食品和药物管理局支持使用建模和模拟来建立(虚拟)生物等效性 参考产品和测试产品之间的关系。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临床试验的需要，因此 加快批准负担得起的药品产品。这项拨款提案的主要目的是 是通过增强MPML MechdermA来将体外数据集成到PBPK模型中 模型，定义体外数据使用的最佳实践，并分析和重新考虑研究 用于生成数据的协议。目标1是整理并向公众提供一个 广泛的皮肤渗透性数据数据库，可用于验证和/或优化PBPK 模特们。该数据库还将用于AIM 2，以验证和优化不同 IVPT设置，如不同的膜类型、扩散池类型等。QSARs内置 对于描述药物分配、扩散和结合的MPML MechDermA将是 系统地评估，从而确定最佳表现的组合 QSARs。如有必要，将开发新的QSAR，以改进从头算预测。这个 经过验证的IVPT模块将得到增强，以便为IVPT研究的设计提供信息，包括 受体溶液溶解度和LLOQ需求的估计。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，重点是氢化可的松(HC)和丙酸氯倍他索的四种配方 (CP)。这些数据将在AIM 4中用于开发健壮的PBPK模型，并随后 外推到体内场景，其中识别的文献数据将被利用来验证 健康人群和患病人群的体内模型。在目标5下，内部HC和CP 具有改良配方属性的药物产品将被设计和表征。这些 将使用修改的公式来挑战PBPK模型，这将验证模型的 辨别生物(内)等价性的能力。作为这一目标的一部分，现有的配方模型将 增强的和先进释放技术的模型，如微球和 将对脂质体进行研究。AIM 6涉及辅料/渗透促进剂同时使用 吸收，特别是丙二醇。丙二醇的实验数据 丙酸氯倍他索乳膏(AIM 2)的渗透性将用于同期研究 并使用MPML MechdermA中的赋形剂模型解释这一点。

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.