Effects of Voriconazole Exposure on the Pharmacokinetics of Tacrolimus in Lung Transplantation Patients, Based on Therapeutic Drug Monitoring Data

Tacrolimus and voriconazole are usually used simultaneously in lung transplantations. Voriconazole can increase tacrolimus concentrations by inhibiting the cytochrome P450 (CYP) enzyme, which poses a great challenge for dose adjustment. The aim of this study is to clarify the correlation between voriconazole exposure and tacrolimus trough concentrations (C-0), and to establish a population pharmacokinetic model including voriconazole trough concentrations (VOZ) as a covariate for dose optimization. All data were retrospectively collected from lung transplantation patients who were subjected to therapeutic drug monitoring of tacrolimus and voriconazole. The correlation between C-0 and VOZ or voriconazole daily doses was analyzed by Spearman's correlation. A total of 52 patients accounting for 351 pairs of tacrolimus and voriconazole trough concentrations were included. C-0 and C-0/daily dose of tacrolimus (DD) had a significant correlation with VOZ (P < .01) rather than voriconazole daily doses. A linear one-compartment model with first-order absorption and elimination was used as the basic model for population pharmacokinetic analysis. Body weight (WT), DD, VOZ, and hematocrit (HCT) were included as covariates in the final model. With the increase in voriconazole concentrations, the apparent total clearance (clearance/bioavailability, CL/F) of tacrolimus decreased significantly. The simulation results showed that the highest proportion of C-0 within the target range can only reach <50% when the optimal initial drug regimen was given. Therefore, both tacrolimus and voriconazole concentrations need to be continuously monitored during treatments in lung transplantation patients, and the tacrolimus dose can be optimized according to VOZ based on the established pharmacokinetic model.