Characterizing local and systemic exposure to clobetasol propionate in healthy subjects and patients with atopic dermatitis

Aims: There is a potential risk of systemic side-effects with the use of potent corticosteroids, such as clobetasol propionate (CP). This concern is of particular interest in paediatric patients. The aim of this study was to develop and verify a physiologically based pharmacokinetic (PBPK) model to describe the local and systemic exposure to CP following topical application over a period of up to 4 weeks. Methods: Data from 12 clinical studies in healthy adult subjects and patients with atopic dermatitis (AD) were available for this investigation. A PBPK model including skin barrier impairment was developed to predict the effect of AD lesions on systemic exposure. Simulation scenarios were then evaluated to assess the effect of formulation, skin condition and surface area (5%–60% of body surface area [BSA]) on systemic exposure. Results: The PBPK model described the absorption and disposition characteristics of CP. Mean clearance, volume of distribution (Vss) and renal clearance were 27 L/h, 2.34 L/kg and 0.12 L/h, respectively. The half-life of CP after topical application was significantly longer than after an IV dose (20.8 vs. 5.2 h). Systemic CP concentrations were higher with increasing surface area and skin barrier impairment. However, CP accumulates in the stratum corneum as the skin barrier function improves during treatment. Conclusions: Systemic and local exposure to CP increases with impaired skin barrier in AD and larger application area. Given the recommended maximum dose of 50 g per week, CP should not be applied to an area of more than 30% of the BSA. Availability of this model will allow extrapolation of CP pharmacokinetics from adults to children.