Preclinical Toxicology Testing

Preclinical toxicity testing of new compounds is an essential part of the drug discovery process. Early preclinical toxicity testing studies done with cells and tissues (in vitro) can reveal critical dose-specific toxic effects of new pharmaceutical compounds. The relatively low cost of early preclinical in vitro toxicity studies makes these tests an excellent initial screen of compounds that show the potential to have therapeutic benefits.

The Drug Discovery Process

The drug discovery process is complex and involves numerous iterative steps to develop and optimize a candidate’s therapeutic properties and minimize the potential for adverse effects. Early preclinical **in vitro ****toxicology studies assist in this iterative process by helping researchers first select and optimizing lead pharmaceutical compounds. These **in vitro studies assist researchers by giving organizations valuable toxicity data that can be referenced to refine a compound for more favorable toxicity parameters. This process of optimizing or selecting compounds showing favorable toxicity data helps reduce the risk of late-stage drug failure due to toxicity issues.

Some common assays run early in the drug discovery process include:

• Cell Viability Assessments: generally use a standard ATP or LDH assay to understand how compound toxicity changes as chemistry changes.
• Mitochondrial Toxicity Assessments: screens for xenobiotic-induced mitochondrial impairment.
• Oxidative Stress Assessments: This helps researchers to understand their compound’s potential to cause oxidative stress by measuring the activation of Nrf2, signaling pathways, and target genes are known to be indicators of oxidative stress.
• Phospholipidosis and Steatosis Assessments: screens for drug-induced liver phospholipidosis and steatosis using HepG2 cells.

Depending on the exact compound(s) being tested one, all, or more of the assays listed above could be used to screen for liabilities due to toxicity-related issues. For companies seeking even more detailed information before entering animal studies or the clinic, a panel of these in vitro assays can be run together. In combination with mathematical modeling, these panels of assays can actually estimate if a compound is likely to cause adverse effects in humans or animals.

In Summary

There are many ways in vitro toxicology can be used in preclinical drug discovery from early screens to later stage predictive studies. To understand which in vitro **assays would best address your specific drug discovery questions we recommend contacting a CRO that specializes in in-vitro test systems.