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

Abstract

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 (C0), 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 C0 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. C0 and C0/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 C0 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.

Pharmacokinetic Evaluation of Tacrolimus in Chinese Adult Patients Receiving Voriconazole During the Early Stage Post-Lung Transplantation

“…However, tacrolimus CL/F in the current study was inconsistent with two previous pharmacokinetic studies 37,38 . Chen et al reported that the typical CL/F value was 6.54 L/h, which was much lower than the value obtained in our study (12.85 L/h) after adjusting for tacrolimus daily dose and haematocrit 37 . However, the previous study calculated the CL/F value after 86 POD (ranging from 5 to 937 days), which may explain this difference.…”

“…Our results showed over 10-fold differences in AUC 0 − 12h between patients taking the same tacrolimus dose, highlighting the importance of close monitoring of tacrolimus blood concentration. However, tacrolimus CL/F in the current study was inconsistent with two previous pharmacokinetic studies 37,38 . Chen et al reported that the typical CL/F value was 6.54 L/h, which was much lower than the value obtained in our study (12.85 L/h) after adjusting for tacrolimus daily dose and haematocrit 37 .…”

“…Tacrolimus CL/F decreased with time after transplantation as corticosteroids were tapered and haematocrit and albumin levels increased [39][40][41] . Moreover, the voriconazole dose (400 mg/d) administered in the study by Chen et al was higher than that of our study (200 mg/d), which may have enhanced its inhibitory effect on tacrolimus pharmacokinetics 37,42,43 .…”

Pharmacokinetic Evaluation of Tacrolimus in Chinese Adult Patients during the Early Stages Post-Lung Transplantation

“…A detailed comparison of pharmacokinetics characteristics and patients' demographics among these studies is presented in Table 4. Chen et al, reported that the typical CL/F value of tacrolimus was 6.53 L/h, much lower than that in our study after adjusting for weight, tacrolimus daily dose, and haematocrit [34]. However, in their study, the enrolled patients were a median of 86 days posttransplant (ranging from 5 to 937 days).…”

“…In our study, the median value of T max was 2 h, which was consistent with previous findings in patients soon after lung transplantation [4] and indicated rapid tacrolimus absorption. However, the geometric mean value of CL/F for tacrolimus was 9.95 L/h, which was larger than those in two previous pharmacokinetic studies in Chinese [34,35] and lower than that in Caucasians [36]. A detailed comparison of pharmacokinetics characteristics and patients' demographics among these studies is presented in Table 4.…”