Validating and Optimizing In Vitro Assays for Improved DDI Prediction – assay calibration and time-dependent inhibition

Date: October 24 2019
Presenter(s): Péter Tátrai, PhD

launch Registration

Time:

7:00 am (PDT)

10:00 am (EDT)

3:00 pm (BST)

4:00 pm (CEST)

5:00 pm (IST)

12:00 am (Beijing)

1:00 am (Tokyo, Seoul)

 

Abstract

With a major focus on the in vitro prediction of transporter-based DDI, we at SOLVO are continually finetuning our assays to maximize patient safety while helping the industry to avoid unnecessary in vivo follow-up studies. Calibration of our vesicular transport assays against clinical DDI data suggests this simple and sensitive platform is ideal for pre-screening efflux transporter interactors but is prone to false positives. Ongoing calibration of our monolayer assays is expected to validate this more complex system as a second, tighter filter. Investigation into the substrate dependence of hepatic uptake transporter inhibition assays indicated that rosuvastatin and estradiol 17-β-D-glucuronide are largely interchangeable in evaluating the in vivo relevance of OATP1B interactions, while coproporphyrin I might offer improved specificity. Finally, our recently published data highlight the importance of uptake transporter preincubation in determining physiologically relevant IC50 values, not only for OATPs but also for other transporters including OCTs. We have shown that large and hydrophobic compounds in particular may require extended preincubation to attain full inhibitory potency. Our research efforts fuel the development of more reliable DDI predictions with less false alarms but zero compromise to safety.

Presenter

Péter Tátrai, PhD, Senior Scientist, SOLVO Biotechnology, a Charles River Company

Dr. Tátrai is a Senior Research Scientist at SOLVO. He graduated from the Eötvös University, Budapest, Hungary, in Cell and Developmental Biology, and did his PhD on extracellular matrix biology of chronic liver diseases and liver cancer at the Semmelweis University, Budapest. Following a brief involvement in molecular cancer diagnostics he moved to the Hungarian Academy of Sciences where he worked on the immortalisation and differentiation of adipose-derived mesenchymal stem cells for experimental regenerative medicine. During a 3-year postdoctoral fellowship at the Cancer Research UK Cambridge Institute he studied mouse models of centrosomal disease. He joined Solvo in 2017, where he is responsible for product development as well as research collaborations.