715 Quantitative description of the physiological changes in diseased skin and their incorporation into physiologically based pharmacokinetic models

Abstract

Recently there has been increased effort within the US FDA to facilitate the approval of new generic topical products, many of these drugs are for the treatment of skin disease. Currently, to assess bioequivalence, it is common practise to recruit patients with the skin disease of interest for a clinical end-point study. However, this approach is very costly, time consuming and patient recruitment can be difficult. A potential solution to this problem would be to combine clinical assessment in healthy patients or in vitro characterisation studies with Physiologically Based Pharmacokinetic (PBPK) modelling, a major strength of PBPK modelling is the ability to extrapolate between populations. The Simcyp MPML MechDermA model is able to predict systemic and local concentrations of topically applied drugs in healthy skin. Physiological parameters within the model can be modified to simulate diseased skin. In order to develop virtual populations for a skin disease, quantitative data describing the physiological differences to healthy skin must be obtained. A population describing the physiology of psoriasis vulgaris has been developed and implemented in the Simcyp Simulator, this population takes in to account physiological changes such as corneocyte dimensions, stratum corneum thickness, surface pH, and increased blood flow. The present work outlines the model structure and describes physiological parameters which are modified in psoriasis, as well as some initial verification of model predictions for exposure in healthy vs diseased patients based on data obtained from the literature. Future work will focus on enhancing these population physiology libraries by obtaining new quantitative measures of disease modification as well as development of populations describing the uninvolved skin of these patients, which is often different to that of healthy patients. In addition, new populations are being developed which describe other disease states such as atopic dermatitis and acne vulgaris.