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

• Main Authors: Fatima Zahra Marok, Laura Maria Fuhr, Nina Hanke, Dominik Selzer, Thorsten Lehr
• Format: Article
• Language: English
• Published: MDPI AG 2021-03-01
• Series: Pharmaceutics
• Subjects: physiologically based pharmacokinetic modeling; bupropion; hydroxybupropion; cytochrome P450 2B6 (CYP2B6); drug-drug-interactions (DDIs); drug-gene-interactions (DGIs)
• Online Access: https://www.mdpi.com/1999-4923/13/3/331

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 <i>CYP2B6*1</i>,<i> *4</i>,<i> *5 </i>and<i> *6</i>. 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 AUC_HBup/Bup ratios), 12/13 DDI AUC_HBup/Bup ratios, and 7/7 DDGI AUC_HBup/Bup ratios within 2-fold of observed values. The developed model is freely available in the Open Systems Pharmacology model repository.