A dermal physiologically-based pharmacokinetic (PBPK) model of clobetasol propionate to predict systemic exposure in eczema and dermatitis patients
Janna K Duong (1), Sven van Dijkman (2), Gary Ong (3), Alexandra Marta (3), Oscar Della Pasqua (2, 4)
(1) Clinical Pharmacology Modelling & Simulation, GSK, Australia, (2) Clinical Pharmacology Modelling & Simulation, GSK, UK, (3) Pharma Research and Development, Global Medical, GSK, (4) Clinical Pharmacology & Therapeutics Group, University College London, London, UK.
Introduction: Clobetasol propionate (CP) is a potent topical corticosteroid indicated for the short-term treatment of psoriasis, atopic dermatitis (AD, eczema) and other steroid responsive dermatoses unresponsive to less potent corticosteroids in adults and children (>1 year). Currently, it is available for topical application as CP in aqueous (0.05% w/w cream) and oil-based (0.05% w/w ointment) formulations. Whilst its efficacy and safety profile has been established in randomised clinical trials and large post-marketing data, the extent of skin permeation and resulting systemic exposure following topical application has not been characterised in children. However, skin permeation in the paediatric population (1 – 12 years old) is expected to be higher than in adult patients. Insight into the pharmacokinetic disposition properties of clobetasol in children may support further guidance for its use in the clinic.
Objectives: To develop and verify a dermal PBPK model for CP to describe the systemic exposure in healthy subjects, and subsequently use the model to predict clobetasol concentration vs. time profiles in plasma in adult and paediatric AD patients considering the effect of formulation (cream vs. ointment).
Methods: A PBPK model (Simcyp Simulator V22) for CP was developed using healthy adult PK data (n = 6) following a single intravenous (IV) dose. The multi-phase multi-layer mechanistic dermal absorption model (MPML MechDermA [1]) in Simcyp was used to describe the skin permeation of clobetasol following topical application of the cream and ointment formulations. first, a dermal absorption model for CP cream formulation was developed using plasma clobetasol concentrations following topical application to healthy adults (n = 5; 30 g, whole body application). The dermal parameters were then optimised using clinical data to improve predictions, and the final model was verified using three separate clinical studies in healthy adults following different dosing regimens (single application, multiple once daily dosing, multiple twice daily dosing), in which PK data was collected. Given the availability of the different dosage forms, a second PBPK model was developed for the ointment formulation based on physicochemical and structural (Q3) characteristics of the formulation and healthy adult data (n = 5; 25 g whole-body application). The final ointment PBPK model was used to predict exposure in adults and in children (1 – 12 years) with AD [2]. Predicted concentration vs. time profiles were used to determine the area under the concentration vs. time curve (AUC) ratio (AUCpatients/AUChealthy adults).
Results: A full PBPK model for CP was developed to describe the PK of clobetasol following a single IV dose. There was good agreement in the PK predictions with the observed data (predicted/observed ratio, 0.9 – 1.3). The dermal absorption model parameters were initially estimated using quantitative structural activity relationships, however this overpredicted the observed plasma concentrations of clobetasol. A global sensitivity analysis revealed the stratum corneum (SC) lipid-vehicle partition coefficient (Ksclip/vehicle) and the corneocyte water partition coefficient (Pcorneocyte) to be influential parameters on the PK of clobetasol, which were therefore optimised to improve predictions of skin permeation. There was large variability in the observed systemic exposure of clobetasol in healthy adults, with some individuals showing no detectable drug concentrations after dose. In contrast, the predicted AUC in adult and paediatric (1 – 12 years old) patients with AD was up to10-fold higher than in healthy adults. The increase in exposure was proportional to the body surface affected by AD.
Conclusions: This fit-for-purpose dermal PBPK model described the skin permeation and resulting systemic exposure to clobetasol following IV and dermal doses in healthy adult subjects. The model-predicted increase in systemic exposure in adult and paediatric (1 – 12 years) patients with AD reflects the known changes associated with skin barrier disruption due to the disease, taking into account age-related differences in skin permeation (reduced thickness, decreased hydration). It is envisaged that this model can be used to further assess the effect of varying treatment duration and skin permeation on the systemic exposure of clobetasol in children with AD.
References:
[1] Patel N, Clarke JF, Salem F, Abdulla T, Martins F, Arora S, et al. Multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) model to predict local and systemic exposure of drug products applied on skin. CPT Pharmacometrics Syst Pharmacol 2022 Aug;11(8):1060-84.
[2] Hehir M, Du Vivier A, Eilon L, Danie MJ, Shenoy EV. Investigation of the pharmacokinetics of clobetasol propionate and clobetasone butyrate after a single application of ointment. Clin Exp Dermatol 1983 Mar;8(2):143-51.