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Abstract
Systemic disposition of dermally applied chemicals is often formulation-dependent. Rapid evaporation of the vehicle can result in crystallization of active compounds, limiting their degree of skin penetration. In addition, the choice of vehicle can affect the permeant’s degree of penetration into the stratum corneum. The aim of this study is to build a predictive, mechanistic, dermal absorption model that accounts for vehicle-specific effects on the kinetics of permeant transport into skin. An existing skin penetration model is extended to explicitly include the effect of vehicle volatility over time. Using in vitro measurements of skin penetration by chemicals applied in both a saline and an ethanol solvent, the model is optimized to learn two vehicle-specific quantities: the solvent evaporation rate and the extent of permeant deposition into the upper stratum corneum immediately following application. The dermal disposition estimates of the trained model are subsequently compared against those of the original model using further in vitro measurements. The trained model showed a 1.5-fold improvement and a 19-fold improvement in overall goodness of fit among compounds tested in saline and ethanol solvents, respectively. The proposed model structure can thus form a basis for in vitro to in vivo extrapolations of dermal disposition for skin formulations containing volatile components.
Highlights
Bioavailability may be inferred by training an in silico model of dermal absorption using in vitro skin permeation test data and extrapolating the trained model to predict the disposition of actives in the in vivo setting [1]
We demonstrate the need for the inclusion of vehicle-specific evaporation rates and deposition layer depths in such models by comparing the dermal disposition estimates generated by the Dancik et al [9] model against measurements from sixty-one in vitro permeation tests (IVPTs) conducted in Hewitt et al [5] using multiple solvents
As an outcome of this work, we propose a framework for future inference of in vivo dermal absorption given IVPT data
Summary
Academic Editors: Heather Benson and Maria Camilla Bergonzi. Establishing reliable estimates of the bioavailability of dermally applied chemicals is a requirement for efficacy and risk assessment studies and for subsequent regulatory approval. Bioavailability may be inferred by training an in silico model of dermal absorption using in vitro skin permeation test data and extrapolating the trained model to predict the disposition of actives in the in vivo setting [1]. The reliability of such modelbased approaches, depends on a quantitative understanding of the processes that determine dermal absorption
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