Date: December 05 2017
Presenter(s): Dr Nicole A. Kratochwil
Nicole A. Kratochwil, PhD, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland
Date: 5 December
7:00 am (PDT)
10:00 am (EST)
3:00 pm (GMT)
4:00 pm (CET)
5:00 pm (IST)
12:00 pm (Tokyo)
Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross species metabolism comparison of low clearance drugs as well as induction studies. Here, we present studies comparing different in vitro liver models (HepG2, iPSC-derived hepatocytes, HepaRG™ and HepatoPac®) with respect to their key metabolic activities. Similar metabolic activities were found for the long-term models, HepaRG™ and HepatoPac®, and the short-term suspension cultures when averaged across all 11 enzyme markers, although differences were seen in the activities of CYP2D6 and non-CYP enzymes. HepatoPac® was further evaluated with respect to clearance prediction. To assess the in vitro parameters, pharmacokinetic modeling was applied. The determination of intrinsic clearance by nonlinear mixed-effects modeling in a long-term model significantly increased the confidence in the parameter estimation and extended the sensitive range towards 3% of liver blood flow, i.e., >10-fold lower as compared to suspension cultures. The micropatterned model gave rise to clearance prediction in man within a two fold error for the majority of low-clearance compounds. In addition to clearance prediction, we present how metabolism, active transport, drug-drug interactions and induction may be assessed simultaneously as multiple endpoints in a single in vitro system. Thus, long-term liver models have great potential as translational research tools exploring pharmacokinetics of novel drugs in vitro.
Dr. Kratochwil is biologist by training and received her PhD degree in Pharmaceutical Sciences from the University of Regensburg, Germany. After receiving an EC Marie Curie research training grant, she conducted her postdoctoral studies at the University of Edinburgh, Scotland, contributing to the European tumor targeting research framework by studying photoactivatable anti-cancer drugs. In 1999, she joined Roche Basel, Switzerland, starting her career in the Chemo/Bioinformatics group, followed by different positions in the preclinical DMPK & Safety department. During these years in pharmaceutical industry, she gained a deep knowledge in the process of drug research across multiple disciplines. Currently, her research focuses on the application of advanced, in vitro cellular models for human PK and DDI predictions using modeling & simulation techniques.