This DGI pertains to the interaction between the cytochrome P450 2C19 (CYP2C19) gene and Voriconazole. Voriconazole (brand name Vfend) is used to treat a variety of serious fungal infections. It belongs to a class of drugs known as azole antifungals. It works by stopping the growth of fungi. Extensive literature indicates that patients with specific genetic differences in the CYP2C19 gene may require an increased dose of Voriconazole in order to prevent breakthrough fungal infections.
The CYP2C19 (sounds like “sip-2-C-19”) gene encodes the CYP2C19 enzyme, which is a member of the cytochrome P450 enzyme family. There are different CYP2C19 gene versions, or variants, and each has a different effect on how well voriconazole is metabolized in the body. The variants termed *2, *3, *4, *5, *6, *7, or *8 may result in a non-functioning or low-functioning CYP2C19 protein. Patients who are intermediate metabolizers of voriconazole carry ONE copy of a non-functioning or low-functioning variant in CYP2C19. Patients who are poor metabolizers of voriconazole carry TWO copies of non-functioning or low-functioning variants in CYP2C19. Patients who are intermediate or poor metabolizers demonstrate a reduced anti-platelet effect and exhibit higher risk for adverse cardiovascular events while on voriconazole. Switching therapy is recommended for patients who are intermediate or poor metabolizers.
Studies have shown that patients with non-functioning or low-functioning CYP2C19 variants may be at increased risk for loss of efficacy or adverse drug events because voriconazole does not work as well. (See Supporting Evidence)
Genotyping for CYP2C19 was performed within a high complexity, certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement act of 1988. This validated clinical Laboratory Developed Test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be >99%.
Population Pharmacokinetics of Voriconazole and CYP2C19 Polymorphisms for Optimizing Dosing Regimens in Renal Transplant Recipients.
Lin Xiao-Bin, Li Zi-Wei, Yan Miao, Zhang Bi-Kui, Liang Wu, Wang Feng, Xu Ping, Xiang Da-Xiong, Xie Xu-Biao, Yu Shao-Jie, Lan Gong-Bin, Peng Feng-Hua in British journal of clinical pharmacology (2018)
OBJECTIVE: To characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. Also to explore optimal dosing regimens for patients who developed invasive fungal infections.
METHODS: A total of 105 patients (342 concentrations) were prospectively included in a population pharmacokinetic analysis. Nonlinear mixed effect models were developed with Phoenix NLME software. Dosing simulations were performed based on the final model.
RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 L·h-1 , 169.3 L and 58% respectively. The allele frequencies of CYP2C19*2, *3 and *17 variants were 29.2, 5.2 and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in both intermediate metabolizers and extensive metabolizers. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily, intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily, and extensive metabolizers with 300 mg intravenously twice daily.
CONCLUSIONS: Using the combination of CYP2C19 genotype with postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring, it could help advance individualized treatment in renal transplantation patients with invasive fungal infections.
Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients.
Hashemizadeh Zahra, Badiee Parisa, Malekhoseini Seyed Ali, Raeisi Shahraki Hadi, Geramizadeh Bita, Montaseri Hashem in Antimicrobial agents and chemotherapy (2017)
OBJECTIVE: 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.
METHODS: 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) ( P < 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) ( P < 0.001).
RESULTS: 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.
CONCLUSIONS: 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.