New Poster: Predicting Systemic Concentrations Following Topical Application Using Physiologically Based Kinetic Modelling

Physiologically Based Kinetic (PBK) models are routinely used to predict human kinetic profiles of compounds. Using PBK models it is possible to predict systemic concentrations of xenobiotic compounds from different routes of exposure. Combined with dose-response toxicology data from appropriate in vitro studies this has application in assessing risk of systemic toxicity. The purpose of this study was to assess the accuracy of a PBK modelling approach for predicting plasma concentration time-profiles of topically applied compounds when the input data was generated using non-animal methods. Prediction of maximum plasma concentration (Cmax) and area under the curve (AUC) were compared to the observed kinetics from published clinical studies. Plasma profiles following topical application were predicted using Gastroplus 9.0 PBK software for six compounds (diclofenac, salicylic acid, coumarin, nicotine, caffeine and N,N-diethyl-m-toluamide), and compared with existing clinical kinetic data from topical application studies. Dermal absorption was determined from ex vivo human skin penetration studies. Hepatic clearance was determined using primary human hepatocyte suspension cultures. Plasma protein binding data was taken from the literature or generated using rapid equilibrium dialysis. In all cases experimental data was used from the literature where available but generated if not. The objective of this work was to compare observed clinical measurements to predictions from PBK models built using the methodology that would be applied to a novel chemical for risk assessment. This included taking conservative assumptions such as ignoring renal clearance of parent for all but one chemical. However, the models still showed good predictivity. With the exception of coumarin, where measured concentration includes metabolites, all predicted kinetic parameters are within 4-fold of measured values and the majority within 2-fold. Given the small number of compounds and due to the lack of topical clinical studies reporting measured kinetics, additional data and approaches are required to improve the confidence in predicting systemic concentrations of topically applied compounds. However, the results of this study suggest that PBK modelling is a suitable approach for estimating the internal concentration of compounds applied to the skin.

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