Assessment of penetrant and vehicle mixture properties on transdermal permeability using a mixed effect pharmacokinetic model of ex vivo porcine skin

摘要

The accurate prediction of the rate and extent of transdermal absorption from topical exposure to chemical mixtures would be beneficial in risk assessment and drug delivery applications. The isolated perfused porcine skin flap (IPPSF) has been used as an ex vivo model for assessing transdermal absorption from topical exposures. A mixed effect, pharmacokinetic tissue model was used to model finite dose, transdermal, absorption data from IPPSF experiments for 12 penetrants dosed in up to 10 different vehicles. The model was able to identify permeability constant, while accounting for between and within unit variability, across the entire data set. This approach provides a platform for exploring the relationship between covariates (chemical descriptors and functions thereof) and the model parameters. Successive models were employed that reduced the overall variability in the parameter estimate by modeling the parameters as functions of the covariates. Log k(p) was initially modeled as a function of LogP and MW of the pure penetrant (adjusted r(2)=0.48). The addition of mixture factors to account for the different dosing vehicles further improved the relationship: to r(2)=0.56 with Connolly molecular area (CMA) and r(2)=0.78 with the further addition of total polar surface area difference (TPSAd). The pharmacokinetic model and quantitative structure property relationship (QSPR) developed for the IPPSF may be relevant to clinical transdermal formulation development. Copyright (c) 2016 John Wiley & Sons, Ltd.