Physiologically-Based Pharmacokinetic Modeling for the Prediction of CYP2D6-Mediated Gene-Drug-Drug Interactions

The aim of this work was to predict the extent of Cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interactions (DDIs) in different CYP2D6 genotypes using physiologically-based pharmacokinetic (PBPK) modeling. Following the development of a new duloxetine model and optimization of a paroxetine model, the effect of genetic polymorphisms on CYP2D6-mediated intrinsic clearances of dextromethorphan, duloxetine, and paroxetine was estimated from rich pharmacokinetic profiles in activity score (AS)1 and AS2 subjects. We obtained good predictions for the dextromethorphan-duloxetine interaction (Ratio of predicted over observed area under the curve (AUC) ratio (R_pred/obs ) 1.38-1.43). Similarly, the effect of genotype was well predicted, with an increase of area under the curve ratio of 28% in AS2 subjects when compared with AS1 (observed, 33%). Despite an approximately twofold underprediction of the dextromethorphan-paroxetine interaction, an R_pred/obs of 0.71 was obtained for the effect of genotype on the area under the curve ratio. Therefore, PBPK modeling can be successfully used to predict gene-drug-drug interactions (GDDIs). Based on these promising results, a workflow is suggested for the generic evaluation of GDDIs and DDIs that can be applied in other situations.