A perspective article entitled "Implementing Differentially Pigmented Skin Models for Predicting Drug Response Variability Across Human Ancestries" was published in Human Genomics uncovering insights into the impact of skin pigmentation on drug efficacy and safety.

This article is part of a special issue: “New Approach Methodologies to Address Population Variability and Susceptibility in Human Risk Assessment” - link.

The key points in the manuscript:

• Melanin, the pigment responsible for skin color, shows a surprising affinity for certain drug compounds. While this property is being explored for innovative drug delivery methods, its implications for drug safety and dosing have been largely overlooked.

• Skin pigmentation may act as a "sponge" for some medications, potentially reducing the amount of active drug reaching its intended targets. This raises alarming questions about the efficacy of standard dosing since people vary a lot in their skin tones.

• Current FDA guidelines for toxicity testing fail to adequately address the impact of skin pigmentation on drug interactions. This oversight is particularly concerning given the push for more diverse clinical trials, as outlined in the agency's Diversity Action Plan[1].

• Advanced 3D skin models offer a promising solution, allowing for preclinical testing that accounts for varying skin pigmentation. These models (part of the category “New Approach Methods – NAMs[2]) could provide crucial insights into drug efficacy and safety across people with a variety of skin tones, importantly also reducing the need for animal testing

Addressing Health Equity:

The study highlights a critical gap in current drug development practices, which primarily focus on drug testing in populations of Northern European descent. Despite recent pushes by the US government through new legislation for diversity in clinical trials, the researchers stress the need for a deeper understanding of biological diversity at the molecular and cellular levels.

Innovative Solutions:

The researchers propose utilizing advanced 3D skin models with varying pigmentation levels. These models offer pharmaceutical companies an efficient method to assess drug binding properties across different skin types.

Lead author Dr. Zaaijer, who is a consultant and researcher specializing in diversity, equity, and inclusion (DEI) in preclinical R&D and clinical trials, with affiliations to the University of California Riverside says: "The cosmetics industry has been at the forefront of skin pigmentation research. L'Oréal in particular has undertaken comprehensive research to identify the distinct characteristics of various skin tones, from dark to fair, enabling them not only to understand these differences but also to develop and validate accurate 3D in vitro skin models that faithfully replicate diverse skin types in laboratory conditions." L'Oréal's initial motivation was to develop more effective sunscreen products, but their research may have far-reaching implications.

The company spun out “EpiSkin”, a venture dedicated to distributing these advanced skin models[3]. Together with another company, MatTek, which offers pigmented 3D skin models of various ancestral backgrounds[4], these companies enable with their turn-key cell models academic scientists and pharmaceutical companies to perform standardized and reproducible skin science which is critical for efficient drug development.

Call to Action:

This manuscript advocates that skin pigmentation should be considered as a factor in safety and dosing estimates and offers a practical implementation strategy, even incorporating the power of Artificial Intelligence (AI).

The authors proposes a cost-effective, scalable novel 4-pillar workflow, where 3D skin models and AI play a central role.

“We stand on the brink of a transformative era in the biomedical industry, where embracing inclusivity is not just an option anymore, but a necessity," Dr. Zaaijer asserts. "Skin pigmentation is just one example. Genetic variations among minority groups can lead to starkly different drug responses across races and ethnicities—affecting up to 20% of medications. Yet, our molecular understanding of these differences remains very limited."

References:

[1] https://www.fda.gov/news-events/press-announcements/fda-guidance-provides-new-details-diversity-action-plans-required-certain-clinical-studies

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10902210/#:~:text=On%20September%2029%2C%202022%2C%20the,drug%20safety%20and%20efficacy5.

[3] https://www.episkin.com/RHPE-Pigmented-Epidermis

[4] https://www.mattek.com/mattekproduct/melanoderm/