Latest Research in ADME-Tox Presented at the Cyprotex Workshop in Cambridge, UK

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Our latest ADME-Tox workshop was held on 16th May 2019 at the Babraham Research Campus in Cambridge, UK. We were fortunate to have a great line-up of key opinions leaders speaking from the pharmaceutical and chemical industry as well as academia. Topics covered the latest research in the ADME-Tox field with quantitative IVIVE, new in vitro tools for toxicology testing and the challenges of working with ‘Beyond Rule of Five’ (bRo5) chemistry appearing as key themes.

Dave Hallifax, Research Fellow, from the Centre for Applied Pharmacokinetic Research (CAPKR) at the University of Manchester provided a review of the factors affecting IVIVE for clearance prediction, including the impact of the unstirred water layer, cell permeability and co-factor depletion.

Rob Elsby, Principal Scientist at Cyprotex, and Beth Williamson, Associate Principal Scientist at AstraZenca both focussed on quantitative prediction of drug-drug-interactions (DDI).  Rob introduced a framework for decision-making utilising in vitro data and mechanistic static equations for evaluating DDI risk with common statin co-medications.  In Beth’s presentation, case studies from AstraZeneca were used to demonstrate the value of combining PBPK modelling and simulation approaches to address regulatory questions.

In the Pharma Industry, the chemical landscape is changing with an increasing number of larger molecules which don’t comply with the traditional rules for small molecules such as the Lipinski Rule of Five. Carina Cantrill, Lab Head in the Cellular Transport Group at Roche, presented on some of the challenges involved in assessing permeability for the purpose or predicting oral exposure for molecules which fall in the bRo5 space.

Melanie Sakatis, who is Chair of the GSK Non-Clinical Hepatic Safety Panel, discussed the evolving hepatotoxicity strategy at GSK using multi-parametric mechanistic approaches to reduce attrition due to safety and specifically hepatotoxicity.  Mitochondrial dysfunction is a common mechanism of drug toxicity and Paul Walker, Head of Toxicology at Cyprotex, compared the different approaches for measuring mitochondrial toxicity including the Glu/Gal assay, mitochondrial membrane potential assessment (using HCS) and the Seahorse mitochondrial stress test.  His presentation also covered a novel approach using permeabilised cells and the Seahorse platform to provide more definitive mechanistic information on individual complexes of the electron transport chain.

Understanding exposure is critical to assessing safety across various industries and it was interesting to hear from Sarah Hatherell, a Scientist from Unilever, about how they utilise an exposure driven non-animal safety risk assessment approach for testing ingredients for consumer products. Their approach uses a tiered strategy based on hazard identification (published databases and in silico alerts), pathway identification (mechanistic in vitro outputs) and pathway characterisation (cell-based models).

The presentations and the posters sessions at the Workshop generated considerable interest and discussion. Cyprotex would like to thanks the speakers and delegates who participated in the Cambridge event and we look forward to seeing you at future events!

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