Opportunities for Microphysiological Systems in Toxicity Testing of New Drug Modalities

Area of Science:

• Pharmacology and Toxicology
• Biotechnology and Bioengineering
• Drug Development and Safety

Background:

• Novel drug modalities provide access to previously undruggable targets, offering significant therapeutic potential.
• These new drugs often exhibit complex, unpredictable, and human-specific side effects, posing challenges for pharmaceutical development.
• Traditional animal studies have limited predictive value for human toxicity due to translatability issues, necessitating alternative methods.

Purpose of the Study:

• To review the application of microphysiological systems (MPS) in modeling toxicological processes relevant to new drug modalities.
• To assess the potential of MPS in predicting specific adverse events, including peripheral neuropathy, thrombocytopenia, immune-mediated hepatotoxicity, and cytokine release syndrome.
• To highlight the capabilities of MPS in addressing the limitations of conventional preclinical toxicity testing.

Main Methods:

• Review of existing studies utilizing microphysiological systems (MPS) for toxicological assessments.
• Focus on MPS features enabling in vitro modeling of complex biological responses: adjustable cellular complexity (including immune cells), modifiable tissue architecture, dynamic mechanism monitoring, and multiorgan connections.
• Analysis of MPS performance in the context of four specific clinical adverse events linked to new drug modalities.

Main Results:

• Microphysiological systems (MPS) offer key features for modeling complex toxicological processes, including cellular and tissue architecture customization, dynamic monitoring, and inter-organ system integration.
• MPS have been explored for modeling adverse events such as peripheral neuropathy, thrombocytopenia, immune-mediated hepatotoxicity, and cytokine release syndrome.
• The review indicates that while the use of MPS for new drug toxicity testing is emerging, it demonstrates significant potential.

Conclusions:

• Microphysiological systems (MPS) present a powerful in vitro tool for modeling the complex toxicities associated with novel drug modalities.
• MPS capabilities, such as incorporating immune components and multiorgan connections, are crucial for predicting human-specific adverse events.
• Despite being in early stages, MPS show strong future potential for improving drug safety assessment and overcoming limitations of animal models in pharmaceutical research.