Preclinical drug safety analysis by chemogenomic profiling in the liver.
The economic hurdles of drug development and the emergence of genomic technologies such as chemogenomics are combining to shift the existing paradigms in preclinical drug development. Today, the information gleaned from high content molecular data has begun to augment traditional approaches to the assessment of drug safety. The optimal approach is a hybrid strategy employing chemogenomic data and gene expression-based biomarkers of drug efficacy and toxicity to supplement low content and insensitive methods for risk assessment and mechanistic evaluation of drug candidates. Large reference databases of chemogenomic data are essential to the derivation and validation of accurate and predictive gene expression biomarkers. An example of the development of a predictive biomarker for hepatic bile duct hyperplasia is described herein. As gene expression technologies improve, biomarkers will achieve higher throughput, and become more cost effective and increasingly accurate. This will elevate the value of chemogenomics in drug development, shift attrition to earlier in the process, and reduce the overall cost of drug development. Over the past 2 to 3 years, the transition of chemogenomics from a research tool to a decision-making tool has begun and regulatory agencies are anxiously awaiting implementation of this technology to make faster and more informed evaluations of potential drugs.
Fielden
Mark R
MR
Iconix Pharmaceuticals, Mountain View, California 94043, USA.
Pearson
Cecelia
C
Brennan
Richard
R
Kolaja
Kyle L
KL
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers; D002273:Carcinogens / Q000633:toxicity; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D006965:Hyperplasia; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000187:drug effects; D010597:Pharmacogenetics / Q000379:methods* / Q000706:statistics & numerical data; D012449:Safety
D015415:Biomarkers; D002273:Carcinogens