Supplementary Material for: Evaluation of the effect of clobetasol propionate on circulating cortisol and growth velocity in children with atopic dermatitis: a modelling and simulation study

Background: Children with atopic dermatitis (AD) appear to have higher skin permeation, which may increase the risk of systemic adverse events following administration of potent topical corticosteroids, such as clobetasol propionate (CP). However, the assessment of dermal absorption in a controlled clinical trial in children is not feasible. Using model-based approaches, this study aimed to characterise stratum corneum (SC) and systemic exposure to CP following topical application of the cream formulation, and to investigate its effects on circulating cortisol levels and growth velocity in children with AD. Methods: Physiologically-based pharmacokinetic (PBPK) and pharmacokinetic-pharmacodynamic (PKPD) modelling were utilised to describe the dermal absorption of CP in a virtual cohort of paediatric patients (1 - < 18 years old). Based on a skin impairment model for lesional and non-lesional skin, CP concentrations in the SC and in plasma were described over time. Simulation scenarios were then implemented to evaluate the effect of varying treatment conditions on the systemic exposure to CP, cortisol levels and growth velocity. Subsequently, clinical case scenarios were simulated to illustrate typical cases of AD in the paediatric population. Results: Surface area had the largest impact on the local and systemic concentrations of CP, while body site and age had a minor effect. When comparing similar surface areas and site of application, the dose, dosing regimen (o.d. vs. b.i.d.) and occlusion had no clinically relevant effect on the local and systemic exposure. Assuming a uniform application (1.2 mg/cm2), CP cream can be applied on up to 20% of the body surface area in children with AD over a period of 2 weeks. The short-term use of CP cream had no effect on the growth velocity of children with AD. Discussion: Surface area affected by AD should be considered when assessing the risk of systemic side effects. CP can be applied up to 20% of the BSA of a child (> 1 year old) without clinically relevant changes to circulating cortisol levels. In contrast to the systemic effects of oral corticosteroids, the short-term use of CP has no impact the growth velocity of paediatric subjects with AD.