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

多功能、多用途 基于皮肤生理学的定量工具 药代动力学（PBPK）建模 项目摘要 施用到皮肤的局部药物产品在它们被擦入皮肤时经历实质性的变形。 使用部位：挥发性辅料如水或醇类挥发，药物和辅料 吸收到皮肤里。其结果是皮肤表面上的残留膜， 在一个实施方案中，将组合物和性质与“从管中出来”的起始制剂进行比较。因为 残留膜的停留时间通常比 当变态发生时，药物进入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），并通过 残膜此外，赋形剂和溶剂可改变药物分配到微囊中和微囊中的扩散率。 皮肤，因此直接影响经皮渗透。 这项工作的目的是扩大现有的生理基础的能力， 药物代谢动力学（PBPK）模型模拟药物在皮肤中的吸收和分布，包括 皮肤给药期间和之后制剂的变态，以及 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，以检验PBPK模型， 正确解释了变态动力学、起始产品的相关质量属性 和残留膜，以及辅料和共溶剂对皮肤吸收的影响，将正确 预测皮肤吸收，并将支持仿制外用药的生物等效性评估 产品. 一个系统的系列日益复杂的药品将在质量方面的特点 通过影响（a）动力学和 （B）当产物演变形成药物时的热力学活性， 残留膜，和（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率。将开发新一代皮肤PBPK模型 具有扩展的、基于机械的能力， 质量属性对药物递送的影响。这些模型将通过与 作为本发明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。由此产生的增强型PBPK模型将是有用的工具， 评估不同皮肤病药物产品是否具有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.