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Evaluation of the Effect of Clobetasol Propionate on Circulating Cortisol and Growth Velocity in Children with Atopic
Janna K Duong1, Sven C van Dijkman2, Gary P Y Ong3
1Clinical Pharmacology Modelling and Simulation, GSK, Sydney, New South Wales, Australia.
Insights
Clobetasol propionate (CP) cream can be safely applied to up to 20% of a child's body surface area for atopic dermatitis (AD). Short-term use of CP cream does not impact growth velocity in children with AD.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Dermatology
- Paediatric Medicine
Background:
- Children with atopic dermatitis (AD) have increased skin permeation, raising concerns about systemic side effects from potent topical corticosteroids like clobetasol propionate (CP).
- Assessing dermal absorption of CP in children via clinical trials is challenging.
Purpose of the Study:
- To characterize stratum corneum (SC) and systemic exposure to CP in children with AD using model-based approaches.
- To investigate the effects of topical CP on cortisol levels and growth velocity in paediatric patients.
Main Methods:
- Physiologically-based pharmacokinetic (PBPK) and pharmacokinetic-pharmacodynamic (PKPD) modeling were used to simulate CP dermal absorption in a virtual paediatric cohort (1 to <18 years).
- Skin impairment models for lesional and non-lesional skin were employed to describe CP concentrations in SC and plasma over time.
- Simulation scenarios evaluated the impact of varying treatment conditions on systemic exposure, cortisol levels, and growth velocity.
Main Results:
- Body surface area significantly influenced local and systemic CP concentrations; age and body site had minor effects.
- Dose, dosing frequency (once vs. twice daily), and occlusion did not significantly alter local or systemic exposure when surface area was comparable.
- CP cream can be applied to up to 20% of body surface area in children with AD for 2 weeks without clinically relevant systemic exposure.
- Short-term application of CP cream did not affect growth velocity in children with AD.
Conclusions:
- Consider the affected surface area when evaluating systemic side effect risks of topical CP in children.
- Topical CP application up to 20% of body surface area in children over 1 year old is safe regarding circulating cortisol levels.
- Unlike oral corticosteroids, short-term topical CP use does not impede growth velocity in paediatric patients with AD.
Abstract:
Introduction: 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 (GV) in children with AD.
Methods:
Physiologically based pharmacokinetic and pharmacokinetic-pharmacodynamic modelling were utilised to describe the dermal absorption of CP in a virtual cohort of paediatric patients (1 to <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, circulating cortisol levels, and GV. Subsequently, clinical cases were simulated to illustrate typical cases of AD in the paediatric population.
Results:
Surface area had the largest impact on 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 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 GV of children with AD.
Conclusion:
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 body surface area 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 GV of paediatric subjects with AD.
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