16 Using physiologically based pharmacokinetic (PBPK) modelling and SCHOLZ databank’s MDDI calculator (SDB-MDDI) to predict potential drug-drug interactions (DDI) of psychopharmaceuticals

Introduction Bupropion is occasionally added for augmentation to depression treatments with venlafaxine. Its inhibitory potential to CYP2D6, venlafaxine’s main metabolic pathway, may provoke a higher risk for toxic or adverse drug effects. Therefore, the question arises if a dose reduction is needed.

Methods PBPK modelling with PK-Sim^® and SDB-MDDI calculator predict the possible extent of DDI. Initially, models based on literature were developed. To evaluate the DDI-PBPK model prediction’s expressiveness, 30 trough plasma concentration samples of 11 male and 12 female patients (median characteristics: 50 (range 33–73) years; 90 (57–140) kg; 171 (158–185) cm, 30 (20–47) kg/m²) were extracted from the TDM-databank Konbest. These patients took bupropion and venlafaxine without any relevant comedication.

Results Compared to equally characterized patients, who are not treated with bupropion, TDM data reveals a significant increase of venlafaxine’s median concentration-dose-ratio (C/D) about 134 %. The PBPK model calculates a 3.94-fold increase of venlafaxine’s AUC. Active metabolite O-desmethylvenlafaxine’s C/D decreases significantly about 28.1 % (PBPK-model: AUC – 51.7 %) and active moiety’s C/D increases not significantly about 18.3 % (PBPK-model: AUC + 9.31 %). SDB-MDDI calculator does not indicate a significant pharmacokinetic interaction for the combination.

Conclusion Due to the low increase of AUC and trough concentration of the active moiety it is concluded that the DDI is clinically irrelevant and a dose reduction is not needed. This is consistent with findings of venlafaxine kinetics in CYP2D6 poor metabolizers [1].

Publication History

Article published online:
30 April 2020

• References

• 1 Schoretsanitis G. et al. (2019), Eur Arch Psychiatry Clin Neurosci 269 (07) : 851-857.