Early drug safety evaluation: biomarkers, signatures, and fingerprints.
When target organ toxicity arises in animal models during routine drug safety evaluation, it raises several key questions: Is this target organ toxicity related to the pharmacology? What is the mode of action (MOA)? Is the target organ toxicity relevant to humans? Pathology or prior knowledge of the compound class may provide clues on a possible MOA for toxicity. However, if this deductive approach yields no results, the inductive approach offered by new technologies can generate novel research leads. For example, toxicogenomics can generate a gene expression profile of the toxicity that can be compared with reference compounds or with other candidate drugs. Similarly, proteomic analysis of the protein profile at the toxic vs. the efficacious dose can provide clues on MOA for the toxicity and may allow differentiation of the pathways of the toxic response from those required for pharmacological activity.
Roberts
Ruth
R
Aventis Pharma, Drug Safety Evaluation, Centre de Recherche de Paris, Paris, France. ruth.roberts@aventis.com
Cain
Kelvin
K
Coyle
Beth
B
Freathy
Caroline
C
Leonard
Jean-Francois
JF
Gautier
Jean-Charles
JC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000032:analysis*; D016172:DNA Fingerprinting / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000032:analysis
D015415:Biomarkers; D004364:Pharmaceutical Preparations