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

多功能、多用途的开发和验证 基于皮肤生理学的定量工具 药代动力学 (PBPK) 建模 项目概要 应用于皮肤的外用药品在被擦入皮肤时会发生显着的变形 使用部位：水或酒精等挥发性辅料挥发，药物和辅料 吸收到皮肤中。结果是皮肤表面残留一层薄膜，其性质完全不同。 “从管中出来”的起始配方的成分和特性。因为 残留膜的停留时间通常比其间的时间长得多 发生变态时，药物输送到皮肤将受到复杂的物理控制 变态的化学（即动力学和热力学）以及变态的性质 残膜。此外，赋形剂和溶剂可能会改变药物在药物中的分配和扩散性。 皮肤，因此直接影响经皮渗透。 这项工作的目的是扩展现有的基于生理学的能力 药代动力学 (PBPK) 模型模拟药物在皮肤中的吸收和分布，包括 皮肤施用期间和之后药物产品的变形 关键配方特性（质量属性）的测量。该项目将利用 实验数据，包括新的和来自文献的数据，来检验 PBPK 模型的假设 正确解释变态动力学、起始产品的相关质量属性 和残膜，以及赋形剂和助溶剂对皮肤吸收的影响，将正确 预测真皮吸收并支持仿制药外用药物的生物等效性评估 产品。 一系列日益复杂的系统性药品将在质量方面得到表征 通过影响 (a) 动力学和 变态机制，（b）产品演化形成药物热力学活性 残留膜，以及（c）改变药物的制剂赋形剂和共溶剂的皮肤吸收 皮肤中的分配和扩散性。将开发新一代真皮PBPK模型 具有扩展的、基于机械的能力来解释产品的变形和 质量属性对药物输送的影响。这些模型将通过与中的比较来验证 作为本研究的一部分收集的局部药物产品的体外和/或体内皮肤渗透测量 项目和文献。由此产生的增强 PBPK 模型将成为有用的工具 评估不同皮肤科药品生物等效性或不生物等效性的可能性 基于最少的临床数据，从而减少批准新药产品的时间和成本 应用于皮肤。

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.