Occasional disparity between the animal and human data plus rising public interest and regulatory requirements to reduce animal usage in research combined with high cost and time- consuming attributes of animal experiments have fuelled the development of economically viable and scientifically reliable in silico and in vitro methods to assess dermal drug absorption. Among other modelling approaches physiologically based pharmacokinetic (PBPK) models have a unique advantage in that they consider separately the drug and the formulation characteristics from the underlying physiology and its variability. Hence, they are better positioned to predict the kinetics for a population including inter-individual variability allowing them to be a powerful product performance assessment tool from an industrial and regulatory perspective. The other perceived advantage of PBPK approach is the possibility of extrapolations. Once the model is validated for a particular drug/formulation in one population e.g. healthy volunteer, it can be assessed with confidence for another population e.g. elderly provided the demographical, anatomical, and physiological differences between healthy and elderly populations are well characterised. Simcyp Population-Based ADME Simulator offers flexible and scientifically validated algorithms for various PBPK models including dermal absorption module. The simulator platform has been developed with a main focus on clinical trials simulation incorporating the inter-individual variability during simulations rather than just the average person and is being used by most of the big pharmaceutical companies and regulatory agencies across the world.
We aim to incorporate new mechanisms that play important roles in dermal absorption, namely, skin surface pH, dermal hydration, skin appendages, bonding to keratin, effect of permeability-modifying formulation ingredients and drug-physiology interactions. The physiology data such as thickness, lipid content pH, hydration level, microvasculature and density of hair follicles in skin from various parts of body for healthy volunteer, paediatric, geriatric and other special populations will be collected, verified, analysed and incorporated into the platform. Additionally a deep tissue compartment will be provided to simulate drug permeation into subcutaneous tissue for locally acting drugs at the site of action and link it to the pharmacodynamics model to simulate the drug effect. The performance verification of the developed model and physiology will be carried out and disseminated to the general scientific community through appropriate channels.

Public Health Relevance

The project aims to develop a physiologically-based dermal absorption and disposition model along with the supporting database of physiology and its variability for not only the healthy Caucasian volunteers but also special populations such as paediatric, geriatric, other races such as Asian and diseased population such as Rheumatoid arthritis. The overall goal of the project is to provide a physiologically based pharmacokinetics (PBPK) modelling and simulation platform for the assessment of new product performance and comparison of test products to the reference products considering inter- and intra- individual variability. The performance of the developed model and database will be validated against clinical pharmacokinetics data of the available dermal products.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1-SRC (99))
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Simcyp, Ltd
United Kingdom
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S2 4S-U