Physiologically Based Pharmacokinetic Modeling to Evaluate the Systemic Exposure of Gefitinib in CYP2D6 Ultrarapid Metabolizers and Extensive Metabolizers.

Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase and is used for the treatment of non-small-cell lung cancer (NSCLC) with activating EGFR mutations. Gefitinib is metabolized by CYP2D6 and CYP3A4. This analysis compared the systemic exposure of gefitinib after oral administration in CYP2D6 ultrarapid metabolizers (UM) vs extensive metabolizers (EM). Physiologically based pharmacokinetic (PBPK) modeling was conducted using a population-based simulator. The model was calibrated using itraconazole-gefitinib clinical drug-drug interaction data and validated with gefitinib data in CYP2D6 EM vs poor metabolizers (PM). System components of the PBPK model were evaluated using published clinical metoprolol pharmacokinetic data in CYP2D6 UM, EM, and PM. Our PBPK model predicted a gefitinib geometric least-squares mean area under the plasma concentration-time curve (AUC) from time 0 to 264 hours (AUC(0-264) ) ratio in the presence vs absence of itraconazole of 1.85, similar to the ratio of 1.78 from clinical study data. Predicted and observed metoprolol geometric least-squares mean AUC(0-24) ratios in UM vs EM were also similar (0.46 and 0.55, respectively), suggesting that system components related to CYP2D6 in the PBPK model were properly established. In addition, the PBPK model also captured gefitinib pharmacokinetic profiles in CYP2D6 polymorphic populations. The final PBPK model predicted a decrease in gefitinib AUC of ∼39% in CYP2D6 UM vs EM. Such changes in exposure will have limited impact as the reduced exposure is still above gefitinib's in vitro IC90 for EGFR activating mutations in NSCLC patients.