Formulation toolbox for topically applied drugs to account for physical parameters, dynamic metamorphosis and influence of excipients

项目摘要/摘要 基于生理的药物动力学(PBPK)建模已经成为一种有价值的工具 新药和仿制药产品的药物开发过程。特别是， 仿制药产品可以使用模拟工具来评估虚拟生物等效性 参考产品和测试产品之间的关系。真皮PBPK模型已应用于 通过预测药物在虚拟环境中的皮肤吸收来开发局部制剂 使用真实的生理学数据构建的种群。重要的是要认识到 外用产品在使用后由于配方而立即发生变化 变形，这可能会改变制剂的关键特性。准确地说 模拟药物通过皮肤的渗透，精确的参数化动态变化 在配方变形过程中发生的变化是至关重要的。这笔赠款的一个主要目标是 建议改进集成在MPML MechDermA中的公式参数化 集成动态配方组成和关键质量反馈的模型 使用高级预测方法的属性。另一个主要目标是系统地 通过评估模型对药物变化的解释能力来验证模型的预测能力 并预测这些变化对局部生物利用度的影响。 具体地说，目标1将重点加强公式工具箱，使 输入完整的配方组成数据(Q2)并实施预测方法以 根据已知的Q2表征来估计配方Q3的性质。建议数 框架将用于追求目标2，其中个别挥发性成分将 允许蒸发并动态重新计算公式Q2和Q3指标 实施。除了蒸发，赋形剂通过皮肤吸收的消耗将 根据目标3.商业和定制的脱氧美松药物产品进行调查 以改良配方属性为特征的产品将根据目标4进行设计和表征。 这些公式将对PBPK模型构成挑战，这些模型将用于验证 模型区分配方变化和评估的能力 生物(内)等价性。目标5将重点放在配方后皮肤水合的评估上 应用包括皮肤水合和PBPK模型的开发和验证 从局部药物产品中吸收水分。AIM 6将开发一个用于模拟的模型 微透析和开流微灌注数据；这个模型将被用来模拟 关于体内局部浓度的现有数据，并进一步验证局部浓度预测。

Project Summary/ Abstract Physiologically-based pharmacokinetic (PBPK) modelling has emerged as a valuable tool in the drug development process for both novel and generic drug products. In particular, simulation tools can be utilised for generic drug products to assess virtual bioequivalence between the reference and test products. Dermal PBPK modelling has been applied to the development of topical formulations by predicting drug absorption into skin in virtual populations that are constructed using realistic physiology data. It is important to recognise that topical products undergo changes immediately upon application due to formulation metamorphosis, which may alter the critical characteristics of the formulations. To accurately simulate drug permeation through the skin, precise parameterisation of the dynamic changes that occur during formulation metamorphosis is crucial. A primary objective of this grant proposal is to improve the formulation parameterisation integrated in the MPML MechDermA model by integrating dynamic formulation compositions and feedback to critical quality attributes using advanced prediction methods. The other primary objective is to systematically verify the model’s predictive capability by assessing its ability to account for variations in drug product attributes and to predict the influence of these variations on the local bioavailability. Specifically, Aim 1 will focus on the enhancement of the formulation toolbox by enabling the input of complete formulation composition data (Q2) and implementing predictive methods to estimate formulation Q3 properties based on known Q2 characterisation. The proposed framework will be used in pursuit of Aim 2, wherein individual volatile constituents will be allowed to evaporate and dynamic re-calculation of formulation Q2 and Q3 metrics implemented. In addition to evaporation, the depletion of excipient through skin absorption will be investigated under Aim 3. Commercial and custom desoximetasone drug products featuring modified formulation attributes will be designed and characterised under Aim 4. These formulations will serve as challenges for the PBPK models, which will be used to verify the models’ ability to differentiate between formulation variations and assess bio(in)equivalence. Aim 5 will focus on the evaluation of skin hydration following formulation application involving the development and validation of a PBPK model of skin hydration and absorption of water from topical drug products. Aim 6 will develop a model for simulating microdialysis and open-flow microperfusion data; this model will be leveraged to simulate available data on local concentrations in vivo and further verify local concentration predictions.