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

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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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Correspondence to Ashok Rakhit.

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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

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