Leveraging multi-organ models for drug combination therapy safety.

Area of Science:

• Pharmacology
• Toxicology
• Biomedical Engineering

Background:

• Assessing systemic toxicity of multidrug combinations is critical for personalized medicine.
• Existing methods may not accurately predict organ-specific toxicities or combination effects.
• Clinically relevant timeframes are needed for efficient drug development.

Purpose of the Study:

• To develop and validate a streamlined in vitro platform for assessing systemic toxicity of multidrug combinations.
• To compare the predictive power of different cellular models for drug-induced toxicity.
• To evaluate the organ-specific toxicity profiles of multidrug combinations.

Main Methods:

• Development of a multi-organ in vitro platform using cellular models of kidney, liver, and heart.
• Evaluation of two multidrug combinations (C2 and REMP) using the platform.
• Comparison of toxicity responses between simple cell lines and advanced organoid/spheroid models.

Main Results:

• The platform identified distinct organ-specific toxicity profiles for multidrug combinations.
• Some drug-induced toxicities were exacerbated in combination therapy.
• Advanced models (organoids, spheroids) showed higher sensitivity and better prediction of toxicity severity compared to simple cell lines.
• C2 combination demonstrated significantly higher toxicity in kidney organoids and differentiated hepatocyte spheroids compared to simpler cell models.
• Lactate dehydrogenase release indicated significant toxicity for C2.

Conclusions:

• Biologically relevant in vitro platforms are essential for accurate systemic toxicity assessment of drug combinations.
• Simple cell lines may underestimate the severity of drug-induced toxicity.
• The developed platform shows translational potential for early-stage toxicity screening in personalized cancer therapy development.