Development and Validation of a Multi-functional, Multi-purpose Quantitative Tool for Dermal Physiologically-Based Pharmacokinetic Modeling

多功能多功能车床的研制与验证 基于真皮生理学的定量工具 药物动力学(PBPK)模型 项目摘要 用于皮肤的局部药物产品在摩擦到皮肤上时会发生实质性的变形 应用场所：挥发性辅料，如水或醇蒸发，以及药物和辅料 吸收到皮肤中。结果是皮肤表面的残留膜有很大的不同 “从试管中出来”的初始配方的组成和性能。因为 残留膜的停留时间通常比 变态发生时，药物进入皮肤会受到复杂的物理控制 变态的化学(即动力学和热力学)和 残留胶片。此外，赋形剂和溶剂可能会改变药物在体内的分配和扩散。 因此，对皮肤的渗透有直接影响。 这项工作的目标是扩展现有的基于生理的 药物动力学(PBPK)模型模拟药物在皮肤中的吸收和处置，包括 药物产品在皮肤使用过程中和之后的变形 关键配方特征(质量属性)的测量。该项目将利用 实验数据，无论是新的还是来自文献的，以测试假设的PBPK模型 正确地解释了变形动力学，解释了起始产品的相关质量属性 和残膜，以及对于辅料和助溶剂对皮肤吸收的影响，都会正确 预测皮肤吸收并将支持仿制药的生物等效性评估 产品。 一系列日益复杂的系统性药品将以质量为特征 通过影响(A)动力学和药物吸收而对药物吸收有显著影响的属性 变态机制，(B)药物热力学活性，因为产物进化形成 (C)制剂辅料和可更换药物的共溶剂的皮肤吸收 皮肤中的分隔性和扩散性。将开发新一代真皮PBPK模型 具有扩展的、基于机械的功能，可解决产品变形和 质量属性对药物传递的影响。这些模型将通过与In 收集的局部药物产品的体外和/或体内皮肤渗透性测量 项目和文献中的内容。由此产生的增强的PBPK模型将是以下方面的有用工具 评估不同皮肤科药物产品生物等效性的可能性 基于最少的临床数据，从而减少了批准新药产品的时间和成本 适用于皮肤。

DEVELOPMENT AND VALIDATION OF A MULTI-FUNCTIONAL, MULTI-PURPOSE QUANTITATIVE TOOL FOR DERMAL PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODELING Project Summary Topical drug products applied to skin undergo substantial metamorphosis as they are rubbed into the application site: volatile excipients like water or alcohols evaporate, and drug and excipients absorb into the skin. The result is a residual film on the skin surface that has quite different composition and properties to the starting formulation that “came out of the tube”. Because the residence time of the residual film is typically much longer than the period during which metamorphosis occurs, drug delivery into the skin will be controlled both by the complex physical chemistry of the metamorphosis (i.e., the kinetics and thermodynamics) and by the nature of the residual film. In addition, excipients and solvents may alter drug partitioning into and diffusivity in the skin and therefore impact directly on percutaneous permeation. The objective of this work is to expand the capabilities of an existing physiologically based pharmacokinetic (PBPK) model simulating drug absorption and disposition in the skin to include metamorphosis of the drug product during and following skin application together with measurements of key formulation characteristics (quality attributes). The project will utilize experimental data, both new and from the literature, to test the hypothesis that a PBPK model that accounts correctly for metamorphosis kinetics, for relevant quality attributes of the starting product and residual film, and for the impact of excipients and co-solvents on skin absorption, will correctly predict dermal absorption and will support the bioequivalence assessment of generic topical drug products. A systematic series of increasingly complex drug products will be characterized in terms of quality attributes that have a significant impact on drug absorption by affecting (a) the kinetics and mechanism of metamorphosis, (b) drug thermodynamic activity as the product evolves to form the residual film, and (c) skin absorption of formulation excipients and co-solvents that change drug partitioning and diffusivity in the skin. A new generation of dermal PBPK models will be developed with expanded, mechanistically based capabilities accounting for product metamorphosis and the impact of quality attributes on drug delivery. These models will be validated by comparisons with in vitro and/or in vivo skin permeation measurements of topical drug products collected as part of this project and from the literature. The resulting enhanced PBPK models will be useful tools for assessing the likelihood that different dermatological drug products are or are not bioequivalent based on minimal clinical data, thereby reducing the time and cost to approve new drug products applied to skin.