Traditionally, ADME testing has relied on animal models and in vitro cell cultures. However, these approaches often fail to accurately replicate human physiology, leading to poor translatability of results.

With increasing regulatory pressure and the need for more predictive models, ex vivo human skin platforms like HypoSkin^® are emerging as an innovative tool supporting ADME testing. By using real human skin, these models provide highly relevant metabolic and absorption data, making them a valuable asset in pharmaceutical research.

ADME testing evaluates how a drug is absorbed, distributed, metabolized, and excreted, ensuring it reaches its target effectively while minimizing toxicity. Regulatory bodies like the FDA and EMA require robust ADME data for drug approval, making it essential for any new drug to reach the market.

In the context of topical formulations, absorption refers to the penetration of the drug through the skin layers into systemic circulation. Injectable formulations (e.g. transdermal patches, subcutaneous injection) absorb through the diffusion of the compound into the extravascular skin tissue, by passage through the vessel wall, and by capillary blood perfusion, with absorption rates varying by administration route. Once absorbed, the drug is distributed throughout the body via the bloodstream. For both topical and injectable formulations, distribution is influenced by factors such as blood flow, drug-protein binding, and tissue permeability. Metabolism involves the biochemical modification of the drug, often by liver enzymes. For skin-administered compounds, some metabolism may occur in the skin before systemic absorption, potentially affecting bioavailability. Excretion is the process through which the drug and its metabolites are eliminated from the body. The rate of excretion affects the drug’s half-life and duration of action.

For topical drugs, the goal is to optimize skin penetration while limiting systemic absorption. For injectables, ADME considerations help refine dosing and minimize interactions. Understanding skin metabolism is crucial to preventing ineffective formulations, unwanted side effects, or toxicity—factors that can delay approval and market success.

Historically, researchers have used animal models (e.g., pig or rodent skin), 2D cell cultures, and reconstructed skin models for ADME testing. While in vitro cell-based models are commonly used for initial ADME screening due to their simplicity and cost-effectiveness, animal models, which offer a more comprehensive system that allows for whole-body drug disposition, are generally utilized in the later stages of ADME testing.

However, each of these methods comes with significant limitations:

• Animal models: Differ in skin structure, enzyme expression, and barrier function, leading to inaccuracies in ADME profiles. They also present ethical concerns, regulatory restrictions, and high costs.
• 2D cell cultures: Lack a full epidermal and dermal structure, leading to unrealistic absorption and metabolism data.
• Reconstructed skin models: More representative of human skin but lack the complexity of living systems, including functional immune cells and a complete extracellular matrix.

Ex vivo human skin models, such as HypoSkin^®, bridge the gap between in vitro and in vivo testing. Derived from real donated human skin, these models maintain the full epidermal, dermal, and immune system architecture, providing:

• Physiologically relevant tissue environment and skin metabolism.
• Realistic penetration and distribution profiles for small and large molecules.
• More predictive responses than animal or cell models.
• Scalability for multiple conditions and formulations.
• Ethically sound, animal-free testing aligning with regulatory trends.

However, they are limited to skin-specific applications and cannot fully replicate systemic ADME processes.

HypoSkin^® is derived from real human donors, preserving both the epidermal, dermal, and hypodermis layers, which are essential for accurate skin absorption and metabolism studies. Unlike reconstructed models, HypoSkin^® retains functional immune cells, allowing researchers to assess immune-related responses in a physiologically relevant environment. Additionally, it maintains metabolic activity comparable to human skin, ensuring reliable predictions of drug biotransformation.

HypoSkin^® allows for the evaluation of drug absorption through different routes of administration:

• Subcutaneous injections: The model can withstand injection of up to 125 µL of liquid formulation into the adipose tissue (hypodermis layer).
• Intradermal injections: Enables testing of drugs delivered directly into the dermis.
• Topical applications: Suitable for assessing absorption of compounds applied to the skin surface.

• Biodistribution studies: HypoSkin® enables tracking the distribution and localization of substances after administration, providing insights into therapeutic effects and off-target interactions.
• Tissue penetration: Researchers can observe how drugs distribute through the different layers of skin (epidermis, dermis, and hypodermis).

• Drug metabolism studies: The model allows for the evaluation of drug processing within human skin, providing essential pharmacokinetic data.
• Metabolic stability: Researchers can assess the stability of compounds in the presence of skin enzymes and metabolic processes.

While direct excretion studies may be limited in an ex vivo model, HypoSkin^® can provide insights into:

• Local clearance mechanisms within the skin
• Potential accumulation of drugs or metabolites in skin tissues

By providing a physiologically relevant human tissue environment, HypoSkin^® offers a valuable tool for generating human-relevant data in the early stages of drug and vaccine development, potentially reducing the need for animal testing and improving the predictive accuracy of non-clinical studies.

Regulatory agencies, including the FDA and EMA, are encouraging the use of non-animal models in drug development¹. New Alternative Methods (NAMs) including ex vivo human skin models like HypoSkin^® are increasingly recognized for their ability to provide high-quality data on absorption, metabolism, and safety without the ethical and translatability issues of animal testing².

In the fast-paced and demanding landscape of the life sciences industry, the need for rapid, dependable, and human-relevant data has never been greater. Companies that are adopting ex vivo human skin models are finding themselves at a distinct advantage, offering a more accurate and predictive representation of human biology compared to traditional animal testing or cell-based assays. The adoption of NAMs including ex vivo human skin models by regulatory agencies represents a paradigm shift in the life sciences industry, paving the way for a future where product development is faster, safer, and more human-centric.

The apparition of ex vivo human skin models is advancing ADME research in pharmaceuticals. Using HypoSkin^®, researchers can obtain predictive, ethical, and scalable data, ensuring better decision-making and product safety.

Ready to optimize your ADME studies with real human skin? Contact us today to learn how HypoSkin^® can advance your research.

1. Replacing Animals in Regulatory Testing and Scientific Research: Where Are We?
2. Potential Approaches to Drive Future Integration of New Alternative Methods for Regulatory Decision-Making