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Session 8

Towards widespread application of mechanistic approaches for identifying cardiotoxicity

Programme of the Session

  • How could mechanistic approaches improve risk assessment and advance the 3Rs? 
    Helen Prior

    National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), London, United Kingdom

  • Comprehensive target analysis by label-free cell microarray profiling and systematic knowledge acquisition to accelerate AOP development
    James Sidaway
    Phenotox Ltd, Bollington, United Kingdom
  • Human Stem Cell Research for Potential Drug-induced Cardiac Arrhythmias and neuronal side effects: Janssen’s Strategy
    Hua Rong Lu, Ivan Kopljar, Kreir Mohamed, Ard Teisman, David J Gallacher

    Global Safety, Pharmacology, Discovery Sciences, Janssen R&D (JNJ), Beerse, Belgium

  • Development and application of an adverse outcome pathway for cardiotoxicity 
    Jochem Louisse1, Helen Prior
    1Division of Toxicology, Wageningen University and Research, Wageningen, Netherlands; 2National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), London, United Kingdom
  • Bridging the gap from current practice towards wider application of mechanistic approaches
    Mark Holbrook 
    VAST pharma solutions, Harrogate, United Kingdom

Session Abstract

Cardiotoxic side effects, which are often only identified late in development during human clinical trials, are a major cause of drug attrition. Currently high numbers of in vivo tests are undertaken to assess potential for cardiotoxicity. Improved predictions could result in cardiovascular liabilities being detected earlier in the drug development process, and may therefore reduce the number of compounds that are destined to fail in the clinic from entering the cascade of regulatory tests. Non-traditional methods (e.g. in vitro or in silico approaches) offer the prospect to improve the mechanistic understanding by which drugs exert cardiotoxic effects, and have potential to be utilised within more predictive, human-relevant testing strategies. Increased understanding of the mechanisms underlying cardiotoxicity will also inform and support the development of new, more predictive assays. This session will outline some of the non-animal approaches that are being developed and utilised to increase the understanding of mechanisms of cardiotoxicity, and which can ultimately be used as part of the safety assessment process. These types of approaches have potential to be applied across the pharmaceutical industry. Dr Helen Prior will provide an opening presentation outlining the drivers and benefits of moving towards mechanism-based approaches for safety assessment. Dr James Sidaway and Dr Hua Rong Lu will outline new technologies that are being applied to determine the safety of new candidate compounds. Dr Jochem Louisse will summarise the progress of an ongoing cross-industry/academia project to develop an AOP in cardiotoxicity. Dr Mark Holbrook will conclude the session by providing an overview of the next steps that are needed to enable a transition away from a reliance on traditional in vivo tests, towards widespread application of mechanistic approaches in cardiotoxicity testing and a more streamlined drug development process.
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