Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients

The aim of this study was to investigate the variability of the voriconazole plasma level and its relationships with clinical outcomes and adverse events among liver transplant recipients to optimize the efficacy and safety of their treatment. Liver transplant recipients treated with voriconazole were included, and voriconazole trough levels were quantified by a validated high-performance liquid chromatography method. Cytochrome P450 genotypes for CYP2C19 were evaluated in allograft liver tissues. A total of 832 voriconazole trough levels from 104 patients were measured. Proven, probable, and possible invasive fungal infections were reported for 8/104 (7.7%), 42/104 (40.4%), and 54/104 (51.9%) patients, respectively. Receiver operating characteristic (ROC) curve analysis indicated that trough concentrations of >= 1.3 mu g/ml minimized the incidence of treatment failure (95% confidence interval [CI], 0.68 to 0.91 mu g/ml) (P < 0.001) and that those of <5.3 mu g/ml minimized the incidence of any adverse events (95% CI, 0.83 to 0.97 mu g/ml) (P < 0.001). Voriconazole trough levels were significantly higher for heterozygous extensive metabolizers, poor metabolizers, and individuals receiving coadministration with proton pump inhibitors. For ultrarapid metabolizers, oral administration of voriconazole, and concomitant use of glucocorticoids, voriconazole blood concentrations were significantly reduced. Furthermore, there was no statistically significant association of patient age, weight, or gender or coadministration of tacrolimus and cyclosporine with the voriconazole trough level. In conclusion, the results of our analysis indicate large inter-and intraindividual variabilities of voriconazole concentrations in liver transplant recipients. Voriconazole trough concentrations of >= 1.3 mu g/ml and <5.3 mu g/ml are optimal for treatment and for minimization of adverse events. Optimization of drug efficacy and safety requires the use of rational doses for voriconazole therapy.