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