Review on Optimising your ADME-Tox Operations

Drug-induced toxicity has surpassed poor ADME properties as the main cause of late stage attrition and withdrawal from the market. The monetary cost for clinical failure or market withdrawal is enormous, often in the billions of dollars. Sometimes, the costs are greater, with patient mortality resulting from toxicity of either experimental or marketed drugs.

Cyprotex’s CSO, Clive Dilworth, PhD, recently participated in a panel discussion held by Genetic Engineering News (GEN), on current approaches and emerging technologies in in vitro ADME-Tox assessment, with the specific goal of reducing late stage failure. The mechanism of toxicity can vary, and GEN sought comment on assessment of two primary causes; genotoxicity leading to carcinogenicity and hepatotoxicity.

In talking about genotoxicity, Dr. Dilworth differentiated between the cosmetics and pharmaceutical industries. In cosmetics, in vitro and in silico test methods are becoming the standards, especially the use of reconstructed human epidermis (RHE) models, as animal testing bans are becoming increasingly common. By contrast, pharmaceuticals require a level of in vivo testing, but only after extensive in vitro evaluation. Amongst many possible test methods, high content screening for toxicological biomarkers are an efficient way to assess genotoxic risk.

Dr. Dilworth also comments on high content screening, or HCS, being a valuable tool for hepatotoxicity prediction. Such methods can use either 2D or 3D cellular models, often utilising human derived cell lines or primary human hepatocytes. Due to their human origin these in vitro models often recapitulate clinical data more closely than preclinical animal models. Three-dimensional cellular models are an exciting innovation because they can be cultured using multiple cell types and closely resemble specific organ tissue. The technology for 3D in vitro assays is expanding rapidly. As well as being amenable to high content screening, 3D cellular models are proving to be more physiologically relevant than 2D models due to the presence of interrelated and interacting cell types.

Finally, looking towards the future of in vitro toxicology, Dr. Dilworth expressed optimism in regard to the potential of stem cells to improve relevancy to the human condition. These cells are demonstrating their utility in the prediction of cardiotoxicity, both in 2D models that use electrophysiology data measured on a microelectrode array (MEA) and 3D models that can assess structural (endothelial) damage. Furthermore, despite the fact that differentiation techniques require further development, there is real potential for iPSC-derived cells to become valuable in metabolic stability and hepatotoxicity prediction.

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