The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition

Eur J Clin Pharmacol. 2008 Jan;64(1):31-41. doi: 10.1007/s00228-007-0396-z. Epub 2007 Nov 14.


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.

Conclusion: 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Area Under Curve
  • Computer Simulation
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Erlotinib Hydrochloride
  • Forecasting
  • Humans
  • Ketoconazole / pharmacology
  • Male
  • Microsomes, Liver / metabolism
  • Middle Aged
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Quinazolines / pharmacokinetics*


  • Cytochrome P-450 CYP3A Inhibitors
  • Enzyme Inhibitors
  • Protein Kinase Inhibitors
  • Quinazolines
  • Erlotinib Hydrochloride
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ketoconazole