title: The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition.
abstract: BACKGROUND
  Erlotinib is an orally active antitumor agent. Analyses in vitro using human liver microsomes and recombinant enzymes showed that erlotinib was metabolized primarily by CYP3A4, with a secondary contribution from CYP1A2.
  
  
  METHODS
  A computer-based simulation model, SimCYP, predicted that CYP3A4 contributed to approximately 70% of the metabolic elimination of erlotinib, with CYP1A2 being responsible for the other approximately 30%. A drug-drug interaction study was therefore conducted for erlotinib and a potent CYP3A4 inhibitor, ketoconazole, in healthy male volunteers to evaluate the impact of CYP3A4 inhibition on erlotinib exposure.
  
  
  RESULTS
  Ketoconazole caused an almost two-fold increase in erlotinib plasma area under the concentration curve and in maximum plasma concentration. This is consistent with the SimCYP prediction of a two-fold increase in erlotinib AUC, further validating a primary (approximately 70%) role of CYP3A4 in erlotinib elimination.
  
  
  CONCLUSIONS
  Prediction of clinically important drug-drug interaction with SimCYP using in vitro human metabolism data can be a powerful tool during early clinical development to ensure safe administration of anticancer drugs, which are often co-administered at maximum tolerated doses with other drugs as part of a palliative treatment regimen.
authors.affiliation: Department of Clinical Pharmacology, F. Hoffmann-La Roche, Inc., Nutley, NJ, USA. Ashok.Rakhit@roche.com
authors.forename: Ashok
authors.initials: A
authors.lastname: Rakhit
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pantze
authors.forename: Scott
authors.initials: S
authors.lastname: Fettner
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Charoin
authors.forename: Myriam
authors.initials: M
authors.lastname: Riek
authors.forename: Bert L
authors.initials: BL
authors.lastname: Lum
authors.forename: Marta
authors.initials: M
authors.lastname: Hamilton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000069347:Erlotinib Hydrochloride; D005544:Forecasting; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole