Skip to main content
SpringerLink
Log in

Therapeutic Drug Monitoring of Voriconazole in the Management of Invasive Fungal Infections: A Critical Review

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kofla G, Ruhnke M. Voriconazole: review of a broad spectrum triazole antifungal agent. Expert Opin Pharmacother. 2005;6(7):1215–29.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  Google Scholar 

  7. Meersseman W, Lagrou K, Maertens J, Van Wijngaerden E. Invasive aspergillosis in the intensive care unit. Clin Infect Dis. 2007;45(2):205–16.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. Hicheri Y, Cook G, Cordonnier C. Antifungal prophylaxis in haematology patients: the role of voriconazole. Clin Microbiol Infect. 2012;18(Suppl 2):1–15.

    Article  CAS  PubMed  Google Scholar 

  10. US FDA. Vfend®. 2008. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021266s023,021267s024,021630s013lbl.pdf. Accessed 19 Feb 2015.

  11. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    PubMed Central  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    CAS  PubMed  Google Scholar 

  30. 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.

    PubMed Central  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

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

  1. College of Pharmacy, Qatar University, PO Box 2713, Doha, Qatar

    Hazem Elewa, Eman El-Mekaty & Kyle John Wilby

  2. Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar

    Ahmed El-Bardissy

  3. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

    Mary H. H. Ensom

Authors
  1. Hazem Elewa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eman El-Mekaty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmed El-Bardissy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary H. H. Ensom
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyle John Wilby
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyle John Wilby.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-015-0297-8

Keywords

Search

Navigation