Abstract
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.
Highlights
The model was extended to describe the effects of cytochrome P450 2B6 (CYP2B6) drug–gene interaction (DGI), drug–drug interaction (DDI), and rifampicin-bupropion CYP2B6 drug–drug–gene interaction (DDGI) on the PK of bupropion and its metabolites
In comparison to the presented work, the model did not incorporate a large amount of data for building and evaluation and did not reflect the effects of different genetic alterations of CYP2B6. These shortcomings, which we consider as necessary elements to qualify the bupropion physiologically based pharmacokinetic (PBPK) model as a part of the CYP2B6 network, were addressed in our model
Even though CYP2B6 hydroxylation plays a major role in the metabolism of bupropion, the implementation of CYP2C19 as minor metabolic pathway was important to sufficiently describe the data including DDIs and DGIs [17,77]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Bupropion is used for the treatment of major depressive disorders and to support smoking cessation [1]. One out of 10 prescriptions among psychotherapeutics was attributed to bupropion in 2018 [2]. In the treatment of depressive disorders, it is either used as monotherapy or in combination with other antidepressant agents, and is administered as oral immediate release, sustained release or extended release tablets [1,3]
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