In Vitro PK Studies in a Long-Term Liver Model
Tuesday, December 5, 2017 - 7:00AM PST, 10:00AM EST, 4:00PM CEST
Presenter: Dr. Nicole Kratochwil - Roche Innovation Center, Basel, Switzerland
Abstract: 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.