A computational workflow for end-to-end simulation of percutaneous absorption.

PURPOSE

Presented is the development of a workflow for end-to-end (e2e) in silico modelling of percutaneous absorption under a range of test conditions, integrating multiple calculation and analysis steps for in-silico simulation of dermal absorption. The aim is to achieve a digital twin that can be used by non-modelling experts to simulate transdermal permeation.

METHODS

A KNIME-based toolbox is used to create the workflow for the E2E in-silico model. The workflow first combines physicochemical property informatics (ChemAxon), molecular dynamics (MD) modelling, and quantitative structure-property relations (QSPRs) to calculate the diffusion and partition properties of permeants in heterogeneous skin layers and complex formulation vehicles. These are then set as input parameters to physiologically based pharmacokinetics (PBPK) model to simulate percutaneous absorption under complex in vitro testing or in vivo exposure conditions set by the end user. Integrated into the PBPK model is the evaporation of volatile permeants and solvents for in vitro unoccluded conditions. The workflow generates a report of the results and records the tested formulation in a database.

RESULTS

The workflow has been tested against several sets of published in vitro permeation test (IVPT) results of percutaneous absorption involving different formulation vehicles. The model predictions of formulation and evaporation effects on percutaneous absorption agreed well with experimental data.

CONCLUSIONS

By automating multiple calculation steps from permeant property, diffusion-partition skin layers and formulation vehicles, to PBPK modelling of dermal absorption, the workflow provides a user-friendly means for non-modelling experts to conduct in-silico simulations of transdermal absorption under various conditions. The workflow is robust to simulate the impact of complex formulation and exposure conditions including evaporation of volatile permeants and solvents on the delivery into the skin.