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

Abstract

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 μg/ml minimized the incidence of treatment failure (95% confidence interval [CI], 0.68 to 0.91 μg/ml) ( < 0.001) and that those of <5.3 μg/ml minimized the incidence of any adverse events (95% CI, 0.83 to 0.97 μg/ml) ( < 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 μg/ml and <5.3 μg/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.

Pharmacokinetics Modeling and Simulation of Voriconazole Dosing and Safety in Patients with Liver Cirrhosis

“…This study found a clear association between voriconazole C min and AEs, and that the threshold C min for identifying patients with a higher risk of AEs was 5.12 mg/L, which is similar to the supratherapeutic target of voriconazole treatment recommended by the guideline from the British Society for Medical Mycology (12). The rate of AEs was higher in this study than previously reported in liver transplant patients (26). A particularly interestingly finding was that 69.0% (20/29) of cases of voriconazole-related AEs developed within the first week after voriconazole treatment, and that the elimination t 1/2 was prolonged, which suggested that implementing accurate initial dose or plasma concentration monitoring as early as possible could avoid the occurrence of AEs.…”

Impact of voriconazole plasma concentrations on treatment response in critically ill patients

“…This study identified a higher percentage of treatment success with voriconazole concentrations above 2 mg/L. Other authors that have analysed the relationship of the effect of the voriconazole concentration on the response to treatment of the IA have identified concentrations >2.0 mg/L in order to maximize the therapeutic potential of this drug . In our study, the lack of data on the minimum inhibitory concentration (MIC) has prevented analysing the impact of the pK/pD parameters in the treatment response.…”

“…11 tential of this drug. 30,31 In our study, the lack of data on the minimum inhibitory concentration (MIC) has prevented analysing the impact of the pK/pD parameters in the treatment response. However, some authors have suggested that a C min /MIC ratio from 2 to 5 is associated with a higher probability of response.…”

Identifying factors affecting the pharmacokinetics of voriconazole in patients with liver dysfunction: A population pharmacokinetic approach

“…Studies have found that CYP2C19 polymorphisms extensively affected voriconazole plasma concentration. 14,19,[48][49][50][51] A recent prospective study in renal transplant recipients 52 showed that CYP2C19 polymorphisms significantly affected the CL of voriconazole; PM patients had significantly higher plasma concentration than both IM patients and EM patients. However, CYP2C19 polymorphisms, it did not affect the pharmacokinetic parameters of voriconazole in this study.…”