Abstract
The broad-spectrum triazole antifungal agent voriconazole is highly efficacious against invasive fungal infections (IFIs) caused by Aspergillus spp. and Candida spp. IFIs are associated with high rates of mortality and morbidity, especially in vulnerable populations such as patients with hematopoietic stem cell transplant as well as other immunocompromised patients. Efficacy of voriconazole in these patients is critical to ensure positive outcomes and reduce mortality. However, a major limitation of voriconazole is the risk of adverse events such as hepatotoxicity and neurotoxicity. As such, therapeutic drug monitoring (TDM) has been suggested as a mechanism to optimize both efficacy and safety. The aim of this review was to summarize and evaluate evidence from the primary literature that assessed TDM outcomes for voriconazole as well as evaluate the association between CYP2C19 polymorphism and the clinical outcomes of voriconazole. Findings showed associations for both efficacy and safety outcomes with measurement of drug concentrations, yet exact targets or thresholds remain unclear. As such, TDM should be reserved for those patients not responding to therapy with voriconazole or those experiencing adverse drug reactions. Future studies should attempt to further define these populations within controlled settings. Studies that evaluated the effect of CYP2C19 genetic polymorphism on clinical outcomes found no significant relationship between CYP2C19 genotype and hepatotoxicity. These negative findings may be due to lack of power, use of phenotypes not well-defined, and the presence of other interacting factors that may impact voriconazole pharmacokinetics. Future well-designed studies are warranted to confirm these findings.
Similar content being viewed by others
References
Kofla G, Ruhnke M. Voriconazole: review of a broad spectrum triazole antifungal agent. Expert Opin Pharmacother. 2005;6(7):1215–29.
Pfaller MA, Diekema DJ, Rex JH, Espinel-Ingroff A, Johnson EM, Andes D, et al. Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints. J Clin Microbiol. 2006;44(3):819–26.
Baddley JW, Stroud TP, Salzman D, Pappas PG. Invasive mold infections in allogeneic bone marrow transplant recipients. Clin Infect Dis. 2001;32(9):1319–24.
Baden LR, Katz JT, Fishman JA, Koziol C, DelVecchio A, Doran M, et al. Salvage therapy with voriconazole for invasive fungal infections in patients failing or intolerant to standard antifungal therapy. Transplantation. 2003;76(11):1632–7.
Enoch DA, Ludlam HA, Brown NM. Invasive fungal infections: a review of epidemiology and management options. J Med Microbiol. 2006;55(Pt 7):809–18.
Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34(7):909–17.
Meersseman W, Lagrou K, Maertens J, Van Wijngaerden E. Invasive aspergillosis in the intensive care unit. Clin Infect Dis. 2007;45(2):205–16.
Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39(3):309–17.
Hicheri Y, Cook G, Cordonnier C. Antifungal prophylaxis in haematology patients: the role of voriconazole. Clin Microbiol Infect. 2012;18(Suppl 2):1–15.
US FDA. Vfend®. 2008. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021266s023,021267s024,021630s013lbl.pdf. Accessed 19 Feb 2015.
Driscoll TA, Yu LC, Frangoul H, Krance RA, Nemecek E, Blumer J, et al. Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults. Antimicrob Agents Chemother. 2011;55(12):5770–9.
Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos. 2003;31(5):540–7.
Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503–35.
Kuo IF, Ensom MH. Role of therapeutic drug monitoring of voriconazole in the treatment of invasive fungal infections. Can J Hosp Pharm. 2009;62(6):469–82.
Owusu Obeng A, Egelund EF, Alsultan A, Peloquin CA, Johnson JA. CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics? Pharmacotherapy. 2014;34(7):703–18.
Park WB, Kim NH, Kim KH, Lee SH, Nam WS, Yoon SH, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis. 2012;55(8):1080–7.
Ueda K, Nannya Y, Kumano K, Hangaishi A, Takahashi T, Imai Y, et al. Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders. Int J Hematol. 2009;89(5):592–9.
Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46(2):201–11.
Miyakis S, van Hal SJ, Ray J, Marriott D. Voriconazole concentrations and outcome of invasive fungal infections. Clin Microbiol Infect. 2010;16(7):927–33.
Dolton MJ, Ray JE, Chen SC, Ng K, Pont LG, McLachlan AJ. Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother. 2012;56(9):4793–9.
Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose PG, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother. 2006;50(4):1570–2.
Troke PF, Hockey HP, Hope WW. Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients. Antimicrob Agents Chemother. 2011;55(10):4782–8.
Chu HY, Jain R, Xie H, Pottinger P, Fredricks DN. Voriconazole therapeutic drug monitoring: retrospective cohort study of the relationship to clinical outcomes and adverse events. BMC Infect Dis. 2013;13:105.
Denning DW, Ribaud P, Milpied N, Caillot D, Herbrecht R, Thiel E, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis. 2002;34(5):563–71.
Matsumoto K, Ikawa K, Abematsu K, Fukunaga N, Nishida K, Fukamizu T, et al. Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes. Int J Antimicrob Agents. 2009;34(1):91–4.
Mitsani D, Nguyen MH, Shields RK, Toyoda Y, Kwak EJ, Silveira FP, et al. Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity. Antimicrob Agents Chemother. 2012;56(5):2371–7.
Racil Z, Winterova J, Kouba M, Zak P, Malaskova L, Buresova L, et al. Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience. Mycoses. 2012;55(6):483–92.
Kim SH, Yim DS, Choi SM, Kwon JC, Han S, Lee DG, et al. Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients. Int J Infect Dis. 2011;15(11):e753–8.
Imhof A, Schaer DJ, Schanz U, Schwarz U. Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring. Swiss Med Wkly. 2006;136(45–46):739–42.
Saini L, Seki JT, Kumar D, Atenafu EG, Cole DE, Wong BY, et al. Serum voriconazole level variability in patients with hematological malignancies receiving voriconazole therapy. Can J Infect Dis Med Microbiol. 2014;25(5):271–6.
Trifilio S, Ortiz R, Pennick G, Verma A, Pi J, Stosor V, et al. Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2005;35(5):509–13.
Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci. 2004;25(4):193–200.
Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317–23.
Hassan A, Burhenne J, Riedel KD, Weiss J, Mikus G, Haefeli WE, et al. Modulators of very low voriconazole concentrations in routine therapeutic drug monitoring. Ther Drug Monit. 2011;33(1):86–93.
Scholz I, Oberwittler H, Riedel KD, Burhenne J, Weiss J, Haefeli WE, et al. Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype. Br J Clin Pharmacol. 2009;68(6):906–15.
Shi HY, Yan J, Zhu WH, Yang GP, Tan ZR, Wu WH, et al. Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism. Eur J Clin Pharmacol. 2010;66(11):1131–6.
Wang G, Lei HP, Li Z, Tan ZR, Guo D, Fan L, et al. The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers. Eur J Clin Pharmacol. 2009;65(3):281–5.
Weiss J, Ten Hoevel MM, Burhenne J, Walter-Sack I, Hoffmann MM, Rengelshausen J, et al. CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol. 2009;49(2):196–204.
Levin MD, den Hollander JG, van der Holt B, Rijnders BJ, van Vliet M, Sonneveld P, et al. Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms. J Antimicrob Chemother. 2007;60(5):1104–7.
Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother. 2014;69:1162–76.
Compliance with ethical standards
No funding was provided for this manuscript. Dr. Elewa, Ms. El-Mekaty, Mr. El-Bardissy, Dr. Ensom, and Dr. Wilby report there are no conflicts of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Elewa, H., El-Mekaty, E., El-Bardissy, A. et al. Therapeutic Drug Monitoring of Voriconazole in the Management of Invasive Fungal Infections: A Critical Review. Clin Pharmacokinet 54, 1223–1235 (2015). https://doi.org/10.1007/s40262-015-0297-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40262-015-0297-8