viernes, 17 de febrero de 2017

NCTR Publications > January-March 2017 Research Highlights

NCTR Publications > January-March 2017 Research Highlights

National Center for Toxicological Researh log with FDA on left side


January 9Effects of Small-Molecule Kinase Inhibitors on Isolated Rat Liver Mitochondria      
Scientists from NCTR and CDER utilized isolated rat liver mitochondria to test 31 FDA-approved small-molecule kinase inhibitors (KIs) for mitochondrial toxicity in vitro and showed that only three (all of which are hepatotoxic in humans) caused mitochondrial toxicity at concentrations equivalent to the therapeutic maximal blood concentrations (Cmax). At this concentration, mitochondrial toxicity showed a 100% positive predictive value (PPV) and a negative predictive value (NPV) of 32%.  Conversely, at 100-fold Cmax, mitochondrial toxicity had a PPV of 72% and a NPV of 33%.  Although in vitro mitochondrial toxicity assessments have been proposed as a useful tool to predict the hepatotoxicity of chemicals, these findings suggest that its predictive power for KI-induced hepatotoxicity in humans is limited to positive predictions at Cmax concentrations.  A manuscript reporting the results of this study is available online at Archives of Toxicologydisclaimer icon. 
For more information, please contact Qiang Shi Ph.D., Innovative Safety and Technologies Branch, Division of Systems Biology, FDA/NCTR or William Mattes Ph.D., DABT, Division Director, Division of Systems Biology, FDA/NCTR.   
January 13FDA Liver Toxicity Working Group Workshop       
NCTR hosted the FDA Liver Toxicity Working Group Workshop on January 9, 2017, at Jefferson Laboratories with additional online conferencing. The workshop provided a forum for toxicologists, clinicians, and regulators from government, academia, and industry to present and discuss current research from clinical, mechanistic, and in silico studies of drug-induced liver injury. The workshop concluded with a panel discussion that addressed the improvement of predictive models and the potential incorporation into regulatory and clinical practice.
For more information, please contact Weida Tong Ph.D., Division Director and Branch Chief, Division of Bioinformatics and Biostatistics, FDA/NCTR.  


February 3New Technologies to Supplement Animal Studies in Evaluating Drugs for Liver Toxicity Risk
Scientists from NCTR, Merck, and LifeNet Health published a review article in Institute for Laboratory Animal Research Journaldisclaimer icon on several new technological developments that might be used to identify drugs with human drug-induced liver injury (DILI) potential. One of the most critical safety issues confronted in drug development is the risk of causing DILI; particularly when traditional animal studies have sometimes failed to identify drugs that caused liver injury in humans. The authors review the history of this issue and discuss new technologies, such as:
  • human cell culture-based systems (e.g., human induced pluripotent stem cell-derived hepatocytes, 3D liver-tissue models, and microfluidic culture systems)
  • new animal models (e.g., humanized liver mouse models)
  • new translational biomarkers
  • computational/predictive models 
While these emerging technologies are still in development, many seem to have promise in screening drugs for potential human DILI risk.
For more information, please contact William Mattes Ph.D., Director, Division of Systems Biology, FDA/NCTR.  

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