The Effects of CYP3A4 Inhibition on Erlotinib Pharmacokinetics: Computer-based Simulation (Simcyp) Predicts In Vivo Metabolic Inhibition

Erlotinib is an orally active antitumor agent. Analyses in vitro using human liver microsomes and recombinant enzymes showed thaterlotinib was metabolized primarily by CYP3A4, with a secondary contribution from CYP1A2.
A computer-based simulation model, SimCYP®, predicted that CYP3A4 contributed to approximately 70% of the metabolic elimination oferlotinib, 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.
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.
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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