Efficient large-scale mechanism-based computation of skin permeability

A drug's skin permeability is a key quantity within dermatological risk assessment as it quantifies the maximal rate of dermal absorption, under steady state conditions, per unit concentration difference across the skin of a topically applied drug. Given descriptors of the permeant, the vehicle, and skin conditions, this paper adopts a systematic approach to efficiently calculate estimates of a topically applied chemical's skin permeability based on mechanistic knowledge of permeability across the elements of a fine spatial discretization of the dermal strata. The permeability estimates are obtained by solving a system of linear equations constructed using an electrical resistor network analogy. Being mechanism based, these estimates can account for skin conditions, heterogenous dermal penetration pathways, and the chemical-dependence and spatial dependence of partitioning and diffusivity.The contribution of this work can be viewed as a mechanistic, numerical, extension of the Potts-Guy relation that augments an open-source dermal PBPK model. Moreover, rather than requiring model simulations of steady state conditions, the approach centers on a direct calculation of permeability based on the mechanistic descriptors of the permeation scenario. The calculation method may therefore be directly integrated into parameter identification, optimization, and sensitivity analysis algorithms. We demonstrate the validity of the method by comparing its permeability predictions with previously reported in silico estimates and in vitro measurements. We additionally illustrate the utility of the method towards the analysis of dermal PBPK models using a minimal example that relates overall skin permeability to the interaction between multiple permeation pathways.