March 06, 2019
Piyush Bajaj, Global Investigative Toxicology, Drug Safety Research and Development, Takeda Pharmaceuticals, Cambridge, MA USA
Date: Monday, March 11
Time: 9:00am – 10:00am
Location: CC Room 337, Baltimore Convention Center
Refreshments will be served during the symposium.
Nephrotoxicity is often among the top five reasons for clinical attrition of compounds. Current in vitro models for detecting and de-risking nephrotoxicity are often inadequate as they lack apical and basolateral transporters responsible for compound uptake and disposition. Additionally, animal models suffer from poor predictivity for their human counterparts. Thus, better and more predictive models are needed which can be used for safety assessment of nephrotoxic compounds.
In this talk, we will discuss the utility of freshly isolated human primary proximal tubule cells (aProximateTM) seeded on TransWell plates for de-risking nephrotoxicity. These freshly isolated proximal tubule cells retained many of the key transport and metabolism functions that are both critical for toxicity and lost during cryopreservation. To assess the utility of aProximate cells, a variety of mechanistically distinct pharmaceuticals were screened using translational safety biomarkers such as KIM-1, NGAL, and Clusterin to detect toxicity in vitro in addition to non-specific end points such as ATP depletion, LDH leakage, and TEER. NGAL showed the highest predictivity followed by other safety biomarkers and LDH. Additionally, the model could also rank-order compounds from the same chemical class according to their clinical risk of causing drug-induced kidney injury. This in vitro platform shows potential to be used as a predictive model for safety assessment of nephrotoxic compounds.
Piyush Bajaj got his PhD from the University of Illinois Urbana Champaign. Dr. Bajaj then did a postdoc at Los Alamos national lab (LANL) developing organs-on-a-chip which could be used for both efficacy and safety assessment. After his postdoc at LANL, Dr. Bajaj moved to Pfizer where he developed/validated protocols for generating human pluripotent stem cell-derived three-dimensional (3D) kidney organoids and was involved in de-risking of potential target organ toxicities using physiologically relevant in vitro models. Dr. Bajaj is now a part of Takeda’s investigative toxicology group where he co-leads liver and kidney de-risking strategies which are applied for proactive management of potential safety liabilities of compounds in the discovery stages.
Monday March 11, 2019 - CC Exhibit hall:
• 1259/P288: Characterization of GCDC transport by human hepatic uptake transporters for in vitro testing purposes. J. K. Zolnerciks, B. Tóth, V. Velky, Z. Tímár, E. Kis, Zs. Gáborik and P. Krajcsi, SOLVO Biotechnology
• 1261/P290: In vitro evaluation of hepatotoxicity by Amiodarone in micropatterned cocultured hepatocytes (HepatoPac) using liver-specific biomarkers. J. K. Zolnerciks, Z. Nerada, R. De Wilde and Z. Gáborik, SOLVO Biotechnology
• 1271/P300: The effect of Kupffer Cells on hepatobiliary transporters in human and rat Hepatocyte/Kupffer co-culture model. J. K. Zolnerciks, K. Jemnitz, Z. Veres, E. Kis, B. Tóth and P. Krajcsi, SOLVO Biotechnology
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