Metabolism enzyme induction-mediated drug-drug interactions need to be carefully characterized in vitro for drug candidates in order to predict in vivo outcomes of safety risk and therapeutic efficiency. Currently, both the FDA and EMA recommend using primary human hepatocytes as the "Gold Standard" in vitro test system for studying the induction potential of candidate drugs on cytochrome P450 (CYP), CYP3A4, CYP1A2, and CYP2B6. However, primary human hepatocytes are known to bear inherent limitations such as limited supply and large lot-to-lot variations which result in an experimental burden to qualify new lots. To overcome these shortcomings, a renewable source of human hepatocytes (i.e., Corning HepatoCells) was developed from primary human hepatocytes and was evaluated for in vitro CYP3A4 induction using methods well established by pharmaceutical industry HepatoCells have shown mature hepatocyte-like morphology, demonstrated primary hepatocyte-like response to prototypical inducers of all 3 CYP enzymes with excellent consistency. Importantly, HepatoCells retain a phenobarbital responsive nuclear translocation of human CAR from the cytoplasm, characteristic to primary hepatocytes. To validate HepatoCells as a useful tool to predict potential clinical relevant CYP3A4 induction, we tested three different lots of HepatoCells with a group of clinical strong, moderate/weak CYP3A4 inducers, and non-inducers. A relative induction score (RIS) calibration curve based approach was used for prediction. HepatoCells showed accurate prediction comparable to primary human hepatocytes. Together, these results demonstrate that Corning HepatoCells is a reliable in vitro model for drug-drug interaction studies during the early phase of drug testing.
- cell models
- cytochrome P450
- drug-drug interactions
- enzyme induction
- in vitro-in vivo prediction (IVIVE)
- The American Society for Pharmacology and Experimental Therapeutics