ADME/Tox


highly specialised within their


testing arena.


Having specialists available internally enables pharmaceutical companies to have more integrat- ed interactions between the ADME and toxicolo- gy testing teams, and the discovery scientists. By allowing all of these groups to discuss findings, goals and outcomes, the discovery process in its entirety can flow smoothly and be more efficient and quickly adapt to changing regulatory guid- ance and trends.


In contrast, smaller biotech and drug develop- ment companies often do not have the funds or resource to warrant an internal team of specialists specifically for ADME and toxicology testing and as such, these companies rely on outsourcing. Therefore the ability to adapt to newer technolo- gies that can help streamline the process and better ensure clinical success is dependent on the various offerings of CROs.


Nonetheless, as with almost any company in the current financial climate, the pharmaceutical industry, small and large, is under increasing pres- sure to lower costs while maintaining high outputs of quality drugs. In order to achieve this, there is a need to lower the cost of research and develop- ment. Better prediction of clinical failures through innovative new processes in ADME and Toxicology settings, that can be implemented earli- er in the development pipeline, could significantly improve overall costs for clinical trials and ulti- mately decrease costs to patients.


Innovation for the future


The FDA has issued guidelines for the use of ADME and toxicology within the drug discovery pipeline, and although it is always recommended to follow such guidelines, it is the ability to innovate that enables drugs to succeed in development. Companies whether small or large need to be able to look beyond the supplied guidelines and visualise the need for testing protocols at various stages of the pipeline, especially earlier on, to really benefit from the data that such techniques supply. Regardless of what the regulatory agencies require, if a technology proves to be more predictive than the currently required regulatory test, it makes sense for its use to be adopted. Ultimately eliminating compound des- tined to fail earlier in development saves money across the board from investors, to large pharma companies, all the way to the amount each patient has to pay for drugs that are determined safe and effective. The recent advancements in new in vitro liver microtissues and improved isolations of the core cellular components of the liver is one area that all drug companies can begin to benefit from.


Drug Discovery World Summer 2017


Conclusion In vitro, human-based ADME and toxicology methods have advanced over recent years, provid- ing researchers with new and effective testing tools to use throughout the drug discovery pipeline, as an indicator of whether the drug candidate will succeed through clinical trials and be brought to the market. The implementation of more tailored, in-depth testing could save pharmaceutical compa- nies both time and resource in the long run. By identifying unsuccessful candidates and ruling them out earlier on, only those compounds most likely to succeed are moved through to the later stages of the pipeline. This more streamlined approach enables the R&D process to be more effective, thus reducing costs and time spent testing unviable candidates, ultimately leading to reduced drug costs for patients in the future. By ensuring that only the most promising can- didates are progressed through to clinical trials, the whole drug discovery pipeline can become more streamlined and efficient. Optimising drug leads early on enables the cost and time implica- tions of progressing unsuccessful compounds through to the later stages of development to be significantly reduced.


DDW


Dr Maureen Bunger is Product Manager for ADMETox and hepatocytes at Lonza, being responsible for Lonza’s product portfolio in these areas. She has extensive knowledge about ADMETox and hepatocytes, and how they can best be used in drug discovery. With more than 20 years of experience in the life science domain, Maureen combines hands-on experience with life science tools, including mass spectrometry, sequencing, molecular biology, stem cells, genetics and animal models, with effective project manage- ment, strategic planning and new product develop- ment. Maureen received a PhD in Molecular Toxicology from the University of Wisconsin- Madison in 2001 and completed postdoctoral training at the National Institutes of Environmental Health Sciences (NIEHS) which is part of the National Institutes of Health (NIH).


References 1 Godoy, P et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non- paranchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signalling and ADME. Arch Toxicol (2013) 87: 1315-1530. 2 Kmiec. Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol (2001) 161: III-XIII, 1-151. 3 Lippincott, JB. Diseases of the liver. (1993) Wiley- Blackwell, Philadelphia. 4 Saunders, WB. Hepatology: a textbook of liver disease. (1996) W B Saunders Co., Philadelphia. 5 Michalopoulos, GK. Liver regeneration. J Cell Physiol (2007) 213:286-300. 6Tanaka, M et al. Liver stem/progenitor cells: their characteristics and regulatory mechanisms. J Biochem (2011) 149:231-239. 7 Liu, ZX et al. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology (2004) 127:1760-1774. 8 Ochi, M et al. Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice. Hepatology (2004) 39:1321-1331. 9 Elaut, G et al. Molecular mechanisms underlying the dedifferentiation process of isolated hepatocytes and their cultures. Curr Drug Metab (2006) 7:629-660. 10 Beigel, J et al. Genomics and proteomics analysis of cultured primary rat hepatocytes. Toxicol In Vitro (2008) 22:171-181. 11 Frazier, JM. The role of mechanistic toxicology in test method validation. Toxicol In Vitro (1994) 8 (4):787-91.


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