. This project will address the need to incorporate formulation drug product quality attributes in dermal physiologically-based pharmacokinetic (PBPK) models for topical dermatological drug products and transdermal delivery systems (RFA-FD-18-019). This will be achieved by a collaborative partnership involving academia, industry and the FDA. We will begin the project using the MechDermA PBPK model, developed by the industry partner, Simcyp, as our core PBPK model. We will collect pertinent literature and undertake appropriate in house studies to define necessary drug product quality attributes from a wide range of formulations to be included in the model. At the same time, we will explore the further development of the model to account for active pharmaceutical ingredient (API) ? product ? skin interactions during the metamorphosis of various products applied to human skin. We will also compare outputs from the MechDermA PBPK model with those obtained from the Roberts team and literature models, especially geometrically complex 3D microstructure diffusion based models. We will also consider the impact of corneocyte wall permeability, binding, SC heterogeneity and dermal blood/lymphatic flow on the dermal absorption for a range of APIs with different physicochemical properties on skin permeation using literature, in silico and in house experimental data. In addition, we will examine the impact of variability in application at a given application site and between individuals in a larger population. These findings will then be used to further develop the MechDermA PBPK model to improve its flexibility, sensitivity and overall predictability. This analysis will then be used to classify APIs for dermal absorption for various products in a scheme like the Biopharmaceutics Drug Classification approach used for oral products. We will also validate/qualify the further developed MechDermA PBPK model using in vivo data sets obtained from the literature, complemented as needed by in vitro skin permeation test (IVPT) studies. Lastly, we will use the model to simulate virtual bioequivalence studies and to evaluate bioequivalence for generic drug formulations. This work will include collecting bioequivalence data for different API types, undertaking a global sensitivity analyses, performing virtual bioequivalence studies in healthy volunteers, and special populations such as elderly or pediatric populations and verifying model performance for various clinical scenarios.
This project will collect and assess dermal and transdermal drug product quality attributes for incorporation into a physiologically based pharmacokinetic software (MechDermA PBPK, Simcyp) that predicts dermal absorption. It is also proposed use literature data and a comparison of the model's predictions with other dermal models to further develop the model and its flexibility, sensitivity and overall predictability. The model will then be used to develop a dermal product classification system for active pharmaceutical ingredients and to undertake virtual bioequivalence studies for a range of populations for possible use in regulatory decisions.
