Animal Models of Human Disease in Drug Safety Assessment

Abstract

-Animal models of human disease have been widely used in drug discovery, but they are rarely utilized in toxicological research and screening (except for transgenic models in carcinogenicity testing). Although genetic and/or acquired pathophysiological alterations associated with a particular disease may greatly exacerbate toxic responses to drugs in certain patient subsets, these pre-existing pathological conditions are usually not considered in preclinical safety assessment. Examples of disease-related determinants of susceptibility include disruption of the cytokine network in pro-inflammatory conditions, mitochondrial alterations and oxidative stress in certain neurodegenerative diseases, altered antioxidant defense in certain viral infections, and altered gene expression and mitochondrial dysfunction in type 2 diabetes. Hence, if cellular stress caused by drugs or metabolites and the disease-related effects are superimposed, then an individual can become sensitized to potential drug toxicity. Animal models of modest inflammation indeed can potentiate the toxicity of certain drugs. Similarly, rodent models of type 2 diabetes predispose the animals to hepatotoxic effects of thiazolidinediones antidiabetics. In conclusion, it is suggested that tailor-made and simplified models be adopted and increasingly used, in spite of clear limitations, as optimal substrates for satellite toxicity studies to facilitate candidate selection, help predict rare and unexpected toxicity, and identify new biomarkers.

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

“…Many techniques are currently available [9,10]. The use of better animal models that replicate the human disease phenotype [44,64] could also unmask latent toxic potentials.…”

Use of Animal Models of Human Disease for Nonclinical Safety Assessment of Novel Pharmaceuticals

“…Using animal disease models in this manner potentially allows for concurrent efficacy and safety endpoint evaluation and also for direct monitoring of improvements in the therapeutic index (Boelsterli 2003) and assessment of on-target safety when healthy nonclinical toxicology species lack the target of interest. Nonetheless, the use of animal disease models in complete safety evaluations in human-enabling nonclinical safety toxicology studies requires a rigorous risk:benefit assessment in the context of drug development.…”

Steatosis: Co-factor in other liver diseases

“…It is possible that impaired energy production and increased oxidative stress in the fatty liver may lead to increased sensitivity to drugs that interfere with mitochondrial function. 81 For example, fatty liver disease has been reported in association with tamoxifen in the treatment of breast cancer. Although the liver injury may be due to drug-induced mitochondrial dysfunction, 82 it occurs more commonly in patients with other risk factors for steatosis.…”