Predicting clearance of metabolically stable compounds using novel human hepatocyte models
Includes a Live Web Event on 05/13/2025 at 11:00 AM (EDT)
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Compounds exhibiting low metabolic clearance are often favored to improve pharmacokinetic profiles and decrease dose. To predict clearance, common experimental techniques include incubations with liver microsomes or cryopreserved hepatocytes in suspension. Hepatocytes in suspension are generally favored as they enable testing of a nearly comprehensive set of metabolic enzymes. However, suspension hepatocytes gradually lose viability in culture, limiting ability to test stable compounds that require longer incubations. Plated hepatocytes will survive for days but lose most drug metabolizing enzyme capacity within 48 hours. In this presentation, methods to overcome loss of phenotype (or increase in assay analytical sensitivity) will be presented. Also, the performance of the models with up to 50 compounds of varying physical chemical properties for predicting clearance will be discussed. The models include hepatocyte suspensions, co-cultures with mouse fibroblasts, tri-cultures with human stromal and endothelial cells, high well density spheroids, and finally a “pre-load” model using mono-culture hepatocytes.
Learning Objectives:
1. Gain an understanding of novel and emerging methods for evaluating hepatic intrinsic clearance of metabolically stable small molecules
2. Learn how suspension hepatocytes, pre-loaded plated human hepatocyte monocultures, co-cultures and high-density spheroid cultures compare to each other
3. Learn how models perform with Lipinski’s Rule-of-Five and beyond Rule-of-Five compounds
4. Gain understanding of the inter-donor reproducibility for selected models
David Kukla, PhD
David Kukla is a Senior Scientist in the Quantitative, Translational, and ADME Sciences department at AbbVie where he uses and develops hepatocyte systems, including complex in vitro models and microphysiological systems aimed at understanding clearance and metabolism pathways. Additionally, his team supports assays to investigate internalization, accumulation, and distribution of small and large molecules within target cells. He received his doctorate in Bioengineering from the University of Illinois at Chicago in the laboratory of Salman Khetani where he developed multiscale human liver platforms for drug development, disease modeling, and regenerative medicine. He received his bachelor’s in Materials Science and Engineering from the University of Illinois at Urbana-Champaign.
David Stresser, PhD (Moderator)
David Stresser is a Research Fellow in the Quantitative, Translation & ADME Sciences department at AbbVie. Prior to joining AbbVie in 2016, he held research, management and business development positions at Gentest Corporation, BD Biosciences and Corning Life Sciences in Woburn, MA. He received post-doctoral training in the laboratory of David Kupfer at the University of Massachusetts Medical School and completed his graduate work in the laboratories of David E. Williams and George S. Bailey at Oregon State University, obtaining a Ph.D. in toxicology. He has co-authored > 60 articles or book chapters on drug metabolism and is an active participant in various pharmaceutical company consortia.
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