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.
