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 ∼70% of the metabolic elimination of erlotinib, with CYP1A2 being responsible for the other ∼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 (∼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.
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Acknowledgements
Medical writing support was provided by Mary Hand, a medical writer at Thomson Gardiner-Caldwell Communications; this support was funded by F. Hoffmann-La Roche.
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Rakhit, A., Pantze, M.P., Fettner, S. et al. The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP™) predicts in vivo metabolic inhibition. Eur J Clin Pharmacol 64, 31–41 (2008). https://doi.org/10.1007/s00228-007-0396-z
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DOI: https://doi.org/10.1007/s00228-007-0396-z