Physiologically Based Pharmacokinetic Modeling of Bupropion and Its Metabolites in a CYP2B6 Drug-Drug-Gene Interaction Network.

The noradrenaline and dopamine reuptake inhibitor bupropion is metabolized by CYP2B6 and recommended by the FDA as the only sensitive substrate for clinical CYP2B6 drug-drug interaction (DDI) studies. The aim of this study was to build a whole-body physiologically based pharmacokinetic (PBPK) model of bupropion including its DDI-relevant metabolites, and to qualify the model using clinical drug-gene interaction (DGI) and DDI data. The model was built in PK-Sim® applying clinical data of 67 studies. It incorporates CYP2B6-mediated hydroxylation of bupropion, metabolism via CYP2C19 and 11β-HSD, as well as binding to pharmacological targets. The impact of CYP2B6 polymorphisms is described for normal, poor, intermediate, and rapid metabolizers, with various allele combinations of the genetic variants CYP2B6*1, *4, *5 and *6. DDI model performance was evaluated by prediction of clinical studies with rifampicin (CYP2B6 and CYP2C19 inducer), fluvoxamine (CYP2C19 inhibitor) and voriconazole (CYP2B6 and CYP2C19 inhibitor). Model performance quantification showed 20/20 DGI ratios of hydroxybupropion to bupropion AUC ratios (DGI AUCHBup/Bup ratios), 12/13 DDI AUCHBup/Bup ratios, and 7/7 DDGI AUCHBup/Bup ratios within 2-fold of observed values. The developed model is freely available in the Open Systems Pharmacology model repository.