Animal models of human disease in drug safety assessment

Area of Science:

• Pharmacology
• Toxicology
• Biomedical Research

Background:

• Animal models are crucial for drug discovery but underutilized in toxicological screening.
• Pre-existing pathophysiological conditions in patients can significantly worsen drug toxicity.
• Current preclinical safety assessments often overlook disease-related susceptibility factors.

Purpose of the Study:

• To highlight the importance of incorporating disease-specific animal models into toxicological research.
• To demonstrate how disease states can sensitize individuals to drug-induced toxicity.
• To advocate for the adoption of tailored animal models for enhanced drug safety evaluation.

Main Methods:

• Review of existing literature on animal models in drug discovery and toxicology.
• Analysis of how specific disease conditions (inflammation, neurodegeneration, viral infections, type 2 diabetes) influence drug responses.
• Examination of case studies where disease models predicted drug toxicity (e.g., inflammation and drug toxicity, type 2 diabetes and hepatotoxicity).

Main Results:

• Disease-related determinants like cytokine network disruption, oxidative stress, and mitochondrial dysfunction increase susceptibility to drug toxicity.
• Animal models of inflammation and type 2 diabetes have successfully demonstrated potentiated drug toxicity (e.g., hepatotoxicity).
• Superimposition of drug-induced cellular stress and disease-related effects sensitizes individuals to adverse reactions.

Conclusions:

• Tailor-made and simplified disease-specific animal models should be increasingly adopted for toxicity studies.
• These models can facilitate candidate selection, predict rare toxicities, and identify novel biomarkers.
• Despite limitations, disease models offer valuable insights for preclinical safety assessment and drug development.