The Evolution of Mitochondrial Toxicity Assessment in Industry

Chapter

Abstract

Safety-related clinical attrition is of particular concern for the pharmaceutical industry due to the significant financial implications associated with late-stage failures. Considerable efforts have therefore been made over the past decade to address this attrition, leading to an industry-wide paradigm shift towards in vitro drug discovery toxicology. Traditionally such toxicological assessments were animal-model focused, with in vitro assays used largely as investigative tools; however, the last decade has seen significant prospective deployment of in vitro toxicology during series selection and lead development. Such in vitro assays have been utilised at this early stage, to better inform early decision making and to facilitate iterative structure-activity relationships, with the objective of progressing only the most promising compounds into animal studies and later into humans. Focus on the early deployment of in vitro models has also been motivated by the observation that several off-target human organ toxicities, particularly liver, are poorly predicted by conventional animal models. During this period, interest in drug-induced mitochondrial dysfunction as a source of compound attrition was generated by literature reports suggesting mitochondrial impairment played a role in organ toxicities associated with post-market drug withdrawals.

Keywords

Isolated mitochondria High throughput soluble sensor Plate reader Mitochondrial uncouplers Mitochondrial inhibitors 

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Luxcel BiosciencesCorkIreland
  2. 2.Pfizer Drug Safety and DevelopmentGrotonUSA

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