(M1530-02-09) Dermal PBPK Model for Psoriatic Skin: Clobetasol Propionate Case Study

Purpose: Psoriasis is a chronic inflammatory skin disease with complex pathophysiology causing changes to the stratum corneum barrier function, modification of the dermal blood flow, and a thickening of the epidermal layer, relative to healthy skin. This disease is typically treated by drug products applied on the outer surface of the skin. It is well accepted that disease-mediated physiological changes can significantly affect the permeation of an active pharmaceutical ingredient (API) through the skin layers. Therefore, it is critical to understand how an API local pharmacokinetics (PK) can differ between healthy and psoriasis conditions, especially in the context of a bioequivalence evaluation between a brand name product and its prospective generic. Dermal physiologically based pharmacokinetic (PBPK) models can provide insight into drug partitioning in skin layers that are not accessible and/or are challenging to sample in humans. The purpose of this study is to demonstrate the utility of a dermal PBPK model in predicting the Clobetasol Propionate (CP) exposure in virtual psoriatic patients. CP was selected as a case study based on the availability of dermal open flow microperfusion (dOFM) data in non-lesional and lesional skin in psoriatic patients [1].

Methods: The Transdermal Compartmental Absorption and Transit (TCAT™) model within GastroPlus® v9.8.3 was previously used to build and validate dermal PBPK model for CP in non-lesional skin [2]. To account for the effect of psoriasis on skin physiology, the default values (i.e., pertinent to normal/non-lesional skin) of epidermal layer thickness, dermal blood flow, and stratum corneum diffusivity were modified considering 4-fold, 5-fold, and 2-fold increase, respectively, reported in literature studies [3 - 8]. Parameter sensitivity analysis (PSA) was performed for each individual parameter, or for combination of parameters to assess the impact of the implemented changes in the skin physiology on model predictions. The model-projected dermis concentrations were compared with the observed CP unbound concentrations in lesional psoriatic skin [1].

Results: Model predictions, after introducing a 4-fold increase on the epidermal layer thickness, a 5- fold increase on dermal blood flow, and a 2-fold increase on stratum corneum diffusivity to the healthy skin physiology model, underpredicted observed CP concentrations in lesional skin, suggesting a need for parameter optimization. The impact on individual parameters was explored via PSA and the results for increased epidermal layer thickness (range 1.5 to 8-fold from default 61.4 μm), dermal blood (range 2 to 10-fold from default 9.89E-02 mL/min/g skin), and stratum corneum diffusivity (range 1.5 to 6-fold from default 1.104E-11 cm²/s) are shown in Figure 1(A), 1(B), and 1(C), respectively. The ranges of individual parameters for PSA were set to reflect the anticipated change for each parameter based on the literature. Increase in epidermal layer thickness (viable epidermis), consistent with histology images [3], was projected to result in decline of CP dermis concentration relative to projection for default thickness for non-lesional skin. However, increases in dermal blood flow and stratum corneum diffusivity were predicted to have significant impact on the CP dermis concentration. These predictions were overlaid in Figure 2 with CP lesional skin concentrations (Day 1) reported in the literature [1].

Conclusion: The dermal PBPK model for psoriatic skin that was developed here considered changes on the stratum corneum barrier function reflected on the API diffusivity through this skin layer, thickening of epidermal layer, and changes to the dermal blood flow. Leveraging the results of PSA allowed for an optimized model in terms of dermal blood flow and stratum corneum diffusivity. The proposed optimized dermal PBPK model better described CP concentrations in lesional psoriatic skin by accounting for disease-related changes to skin barrier function and blood flow increase. Further validation of this in silico tool for psoriatic skin and increase in knowledge in skin physiology changes as a result of disease may support efforts for drug product development in psoriatic patients.

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Acknowledgements: This project was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of financial assistance awards 1 U01 FD006526-01 and 1 U01 FD007320-01 totaling $1M with 100 percent funded by FDA/HHS. The views expressed here do not reflect official policies of the U.S. FDA or the Department of Health and Human Services, nor does any mention of trade names imply endorsement by the U.S. Government.

PSA for Individual Parameters: (A) Viable Epidermis Thickness; (B) Dermal Blood Flow; (C) Stratum Corneum Diffusivity. Note: Dermal Layer 14 Corresponds to the Depth of dOFM probe

Multifactorial PSA for Stratum Corneum Diffusivity and Dermal Blood Flow