The role of investigative molecular toxicology in early stage drug development.
Molecular toxicology, the application of molecular biology principles and technologies to preclinical safety assessment, represents a key tool for understanding mechanisms of toxicity and assessing the risks associated with specific toxicities. The application of gene expression markers to early stage preclinical safety assessment has the potential to impact pipelines in two main areas: lead optimisation and issue management. Lead optimisation focuses on deprioritising leads with significant, development-limiting toxicological liabilities while advancing those compounds with the greatest chance of successfully navigating the gauntlet of preclinical and clinical safety studies. Issue management utilises mechanistic toxicology studies to position non-development-limiting findings prior to the onset of Good Laboratory Practice studies in full development, and can help to identify and validate gene expression markers predictive of adverse events to avoid issues in second-generation projects. In this review, the authors describe the application of molecular toxicology to a standard pharmaceutical testing funnel, provide examples of the successful application of gene expression markers, and discuss the potential for future impact in several broad categories of clinically relevant toxicity.
Gross
Cindy J
CJ
Pharmacia Corporation, Mail Stop TA1, 800 North Lindbergh Blvd, St Louis, MO 63167, USA. jeffrey.a.kramer@pharmacia.com
Kramer
Jeffrey A
JA
D015195:Drug Design; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000633:toxicity*; D008967:Molecular Biology / Q000379:methods; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000639:trends; D014116:Toxicology / Q000379:methods
D015507:Drugs, Investigational