ADME/Tox


Primary human hepatocytes in sandwich culture for five days. © Lonza, Basel, Switzerland


replicate the full liver function. Regulatory agen- cies do not require detailed mechanistic testing in a human model system for toxicity testing, so it is most often not performed. Human cellular toxicity testing that is required is limited to very simple models and tumour cell lines. Toxic drugs that advance through the clinical pipeline often do so because of three main factors: 1. The length of time to generate the toxic response is long and therefore not modelled by the shorter term preclinical and early clinical testing. 2. The toxic response is specific for humans and therefore not captured in preclinical animal testing. 3. The toxic response is rare and population sizes used in preclinical and early clinical studies are too


Primary animal hepatocytes in sandwich culture for two days. © Lonza, Basel, Switzerland


Impacting big pharma It is thought that the regulatory agencies are begin- ning to explore and even embrace more in vitro testing technologies, as evidence continues to mount for their value. This has required a change of mind-set to include seeing each of these new in vitro technology as a functional unit, rather than something that will solve current preclinical testing failures by providing a one-to-one substitution for animal models. All pharmaceutical companies have internal or external groups that address the needs for ADME and toxicology in their drug pipelines. In larger pharma companies, these are often within their own metabolism and toxicology groups of spe- cialists where other discovery project groups within the company send their compounds for testing. Such groups will see every compound in development, enabling them to have a broad overview of the development pipeline, and be


22 Drug Discovery World Summer 2017


small, or not diverse enough to capture the effect. These late-stage failures are very costly, both financially and in terms of patient health. With advances in primary cell culture technolo- gies and bioengineering that enables the recre- ation of human physiology on the benchtop, there are opportunities to fill the gaps in preclinical testing. For the first type of toxicity failure, dura- tion of response, hepatocytes and hepatic micro- tissues can be maintained for >40 days in a spheroid format and fluid flow cultures. For the lack of correlation between human response and animal models, there are examples where micropatterned hepatocyte with fibroblast co-cul- tures and spheroids out-predict animal models for clinical liver toxicity. For larger population-based idiopathic responses, cell culture systems such as iPSC-derived cells can be developed from biobanked tissue sources that number in the 10s of thousands.


There are of course other cell types that are important for ADME and toxicology testing, such as stellate, Kupffer and sinusoidal endothelial cells, which can be coupled in co-cultures to allow the analysis of complex communication networks in vitro. Such an approach could have enormous ben- efits, especially when expanded to couple entire microphysiological systems such as the liver, heart, lung muscle, adipose and kidney. Although years away from reality, the advantages of being able to analyse interactions and the impact of a drug com- pound more holistically across the body could be significant in terms of the future of drug develop- ment methods.


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