A preliminary exploration of liver microsomes and PBPK to uncover the impact of CYP3A4/5 and CYP2C19 on tacrolimus and voriconazole drug-drug interactions

Solid transplant recipients are at increased risk for invasive aspergillosis. Tacrolimus and Voriconazole is one of the most frequently utilized treatments for those recipients with invasive fungal infections. However, it is difficult to use them properly due to the interaction between them. This study aimed to investigate the potential drug-drug interaction between Tacrolimus and Voriconazole by multiple methods, including in vitro liver microsome method and the PBPK(Physiologically Based Pharmacokinetic) model. Midazolam and testosterone were used as probe substrates to evaluate individual differences in CYP3A4/5 metabolic activity. A comprehensive interaction analysis was also conducted based on the STITCH database and the DD-Inter system. Furthermore, a PBPK model was constructed by the data from the literature to simulate the real metabolic process in vivo. The research employed multiple methodologies to demonstrate that the co-administration of Voriconazole significantly enhances Tacrolimus concentrations, considering genotypes and the activity of CYP3A4/5 genotypes. The findings indicated a decrease in the relative percentages of midazolam and testosterone metabolites with increasing Voriconazole concentration. Moreover, the results for residual Tacrolimus in the 30-minute incubation group revealed that Voriconazole exerts a mild inhibitory effect on the in vitro metabolism of Tacrolimus. The STITCH database and DD-Inter system analysis also suggested that Tacrolimus and Voriconazole share a strong association in liver metabolism, most likely interacting with CYP3A4/5 and CYP2C19. Furthermore, the result of PBPK analysis indicated that Tacrolimus AUC increases with Voriconazole co-therapy. Moreover, the AUC of Tacrolimus in intermediate CYP2C19 metabolizers (IM) was the highest at 10.1 µmol·min/L, followed by poor metabolizers (PM) at 8.13 µmol·min/L, and extensive metabolizers (EM) at 2.18 µmol·min/L. And the genotype of CYP3A5 poor metabolizer (PM) had AUC of Tacrolimus at 3.13µmol·min/L and extensive metabolizer (EM) at 2.18µmol·min/L. Microsomal studies, PBPK models, and multiple other analyses have comprehensively elucidated the impact of Voriconazole on Tacrolimus concentrations. These findings can serve as a valuable point of reference for concurrently administering these two medications. These findings also indicate that the genotypes of CYP2C19 play an important role in the development of DDI during concurrent Tacrolimus and Voriconazole treatment, which may have some guidance for clinical medication.