Application Of Metabolomics In Preclinical Drug Safety Evaluation Within The Predtox Consortium

Alexander Amberg

Sanofi-Aventis, Germany

The preclinical drug safety evaluation is an important and critical step in the development of new drugs and a high attrition rate in this phase increases the cost of drug development and time of delivery of innovative medicines to patients. The goal of new technologies is to improve the prediction of drug induced toxicity by new biomarkers and to better understand the mechanisms of toxicity additionally to conventional methods like histopathology, clinical chemistry etc. New “omics” technologies like toxicogenomics, proteomics and metabolomics offer the opportunities to achieve these goals.

PredTox (Predictive Toxicology) as a part of the EU-FP6 InnoMed (Innovative Medicines for Europe) project is a consortium consisting of 13 major pharmaceutical companies, 3 universities and 2 technology vendors. The focus of this consortium is the application of the integrated approach of conventional methods in combination with new “omics” technologies in drug safety evaluation (Further information is available under www.innomed-predtox.com).

The PredTox consortium investigated 14 proprietary compounds that failed due to liver and kidney toxicity in drug development and the 2 reference compounds troglitazone that had been withdrawn from the market due to hepatoxicity and the nephrotoxicant gentamycin. Studies were performed using a harmonized experimental protocol. Groups of 5 male Wistar rats were treated with 2 dose levels for 24 hours, 3 and 14 days including time-matched vehicle controls. Liver, kidney, blood and urine samples were collected for the different analysis. Conventional endpoints, like histopathology and clinical chemistry were investigated together with gene expression analysis using Affymetrix Rat GeneChip RAE 230plus (organs and blood), toxicoproteomic analysis using SELDI (organs and plasma), 2D-DIGE (organs) or 2D-PAGE (urine), and analysis of the metabolic profiling by ¹H-NMR (urine, serum) and LC-MS (urine, serum). All data were implemented into a database for detailed data analysis. Bile duct necrosis, hepatocellular hypertrophy and tubular nephrotoxicity were the most observed histopathological changes together with changes in clinical chemistry parameters. This was also reflected by dose- and time-dependent changes in the expression of genes, proteins and endogenous metabolites for many compounds. The presentation will also show some preliminary results from the reference compound troglitazone.

Further goals of the PredTox consortium will be to identify common genes, proteins and metabolites by cross-compound and cross-omics analysis to better understand pathways changes and mechanism of toxicity and probably to identify new biomarkers of toxicity for the use in preclinical safety evaluation.