title: Drug-drug interaction potential of marketed oncology drugs: in vitro assessment of time-dependent cytochrome P450 inhibition, reactive metabolite formation and drug-drug interaction prediction.
abstract: OBJECTIVE
  To evaluate 26 marketed oncology drugs for time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes. Evaluate TDI-positive drugs for potential to generate reactive intermediates. Assess clinical drug-drug interaction (DDI) risk using static mechanistic models.
  
  
  METHODS
  Human liver microsomes and CYP-specific probes were used to assess TDI in a dilution shift assay followed by generation of K(I) and k(inact). Reactive metabolite trapping studies were performed with stable label probes. Static mechanistic model was used to predict DDI risk using a 1.25-fold AUC increase as a cut-off for positive DDI.
  
  
  RESULTS
  Negative TDI across CYPs was observed for 13/26 drugs; the rest were time-dependent inhibitors of, predominantly, CYP3A. The k(inact)/K(I) ratios for 11 kinase inhibitors ranged from 0.7 to 42.2 ml/min/μmol. Stable label trapping agent-drug conjugates were observed for ten kinase inhibitors. DDI predictions gave no false negatives, one true negative, four false positives and three true positives. The magnitude of DDI was overestimated irrespective of the inhibitor concentration selected.
  
  
  CONCLUSIONS
  13/26 oncology drugs investigated showed TDI potential towards CYP3A, formation of reactive metabolites was also observed. An industry standard static mechanistic model gave no false negative predictions but did not capture the modest clinical DDI potential of kinase inhibitors.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, MS412A, South San Francisco, California 94080, USA. kenny.jane@gene.com
authors.forename: Jane R
authors.initials: JR
authors.lastname: Kenny
authors.forename: Sophie
authors.initials: S
authors.lastname: Mukadam
authors.forename: Chenghong
authors.initials: C
authors.lastname: Zhang
authors.forename: Suzanne
authors.initials: S
authors.lastname: Tay
authors.forename: Carol
authors.initials: C
authors.lastname: Collins
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Galetin
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D003577:Cytochrome P-450 Enzyme System