Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity and outcome in Liver Transplant Patients; an Observational Study [PublishAheadOfPrint]

The aim of this study was to investigate the variability of voriconazole plasma level and its relationship 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 the validated high-performance liquid chromatography method. Cytochrome P450 genotypes of 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 in (8/104, 7.7%), (42/104, 40.4%), and (54/104, 51.9%) patients, respectively. ROC curve analysis indicated that trough concentration ≥1.3 μg/ml minimized the incidence of treatment failure (95% CI 0.68–0.91; P < 0.001), and < 5.3 μg/ml minimized the incidence of any adverse events (95% CI 0.83–0.97; P < 0.001). Voriconazole trough levels were significantly higher in heterozygous extensive metabolizers, poor metabolizers and co-administration with proton pump inhibitors. In ultra-rapid metabolizers, oral administration of voriconazole and concomitant use of glucocorticoids, voriconazole blood concentrations were significantly reduced. Furthermore, there was no statistically significant association of patients' age, weight, gender, co-administration of tacrolimus and cyclosporine with voriconazole trough level. In conclusion, the results of our analysis indicated large inter and intra-individual variabilities of voriconazole concentrations in liver transplant recipients. Voriconazole trough concentrations between ≥1.3 μg/ml and < 5.3 μg/ml are optimal for treatment and minimize adverse events. Optimizing drug efficacy and safety need rational doses for voriconazole therapy.

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