title: Evaluation of Time Dependent Inhibition Assays for Marketed Oncology Drugs: Comparison of Human Hepatocytes and Liver Microsomes in the Presence and Absence of Human Plasma.
abstract: OBJECTIVE
  To evaluate an alternative in vitro system which can provide more quantitatively accurate drug drug interaction (DDI) prediction for 10 protein kinase inhibitors for which DDI risk was over-predicted by inhibition data generated in human liver microsomes (HLM).
  
  
  METHODS
  Three cryopreserved human hepatocyte (hHEP) systems: 1) plated hHEPs; 2) hHEPs suspended in Dulbecco's Modified Eagle Medium (DMEM) and 3) hHEPs suspended in human plasma (plasma hHEPs) were developed to detect CYP3A time dependent inhibition, and the static mechanistic model was used to predict clinical outcomes.
  
  
  RESULTS
  A general trend was observed in the CYP3A inactivation potency (k inact /K I, app ) as HLM > plated > DMEM ≥ plasma hHEPs. Using the static mechanistic model, DDIs predicted using parameters estimated from plated, DMEM and plasma hHEPs had 84, 74 and 95% accuracy (out of 19 clinical interaction studies) within 2-fold of the reported interaction, respectively. They demonstrated significant improvement compared to the DDIs predicted using parameters estimated from HLMs where 58% accuracy was obtained.
  
  
  CONCLUSIONS
  Based on 19 DDIs, plasma hHEPs demonstrate a more reliable clinical DDI prediction for 10 protein kinase inhibitors and prototypical CYP3A time dependent inhibitors.
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California, 94080, USA. mao.jialin@gene.com.
authors: Jialin
authors: J
authors: Mao
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California, 94080, USA.
authors: Suzanne
authors: S
authors: Tay
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California, 94080, USA.
authors: Cyrus S
authors: CS
authors: Khojasteh
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California, 94080, USA.
authors: Yuan
authors: Y
authors: Chen
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California, 94080, USA.
authors: Cornelis E C A
authors: CE
authors: Hop
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California, 94080, USA.
authors: Jane R
authors: JR
authors: Kenny
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D057075:Enzyme Assays / Q000379:methods; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D010949:Plasma / Q000187:drug effects / Q000378:metabolism
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A
keywords: CYP3A; drug–drug interaction; kinase inhibitors; prediction; time dependent inhibition