Skip to main content

Advertisement

SpringerLink
Log in

Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

We investigated the role of therapeutic dose monitoring (TDM) in the treatment of fungal infections with voriconazole through 49 analyses of 34 patients who received treatment for hematologic diseases. Voriconazole concentration was highly variable among patients regardless of renal, liver functions, or age, and the effect of dose enhancement was not constant. This indicates the difficulty of predicting voriconazole concentration without TDM. We evaluated the outcome with the composite assessment system where patients were assumed non-responders when they failed to show improvement in at least 2 of the following 3 criteria: clinical, radiologic, and mycologic. We showed that concentration–response relationship depended on the status of underlying hematologic diseases; this relationship was observed only in cases without refractory hematologic diseases, but not in those with refractory diseases. In the former group, cases with >2 mg/L of concentration were associated with good response to voriconazole. On the other hand, elevation of hepatic enzyme was frequently observed when voriconazole concentration was >6 mg/L. From these results, we concluded that TDM should be executed and targeted to 2–6 mg/L to improve efficacy and to avoid side effects.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus study group. Medicine (Baltimore). 2000;79:250–60. doi:10.1097/00005792-200007000-00006.

    Article  CAS  Google Scholar 

  2. Hachem R, Hanna H, Kontoyiannis D, Jiang Y, Raad I. The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy. Cancer. 2008;112:2493–9. doi:10.1002/cncr.23466.

    Article  PubMed  Google Scholar 

  3. Chamilos G, Luna M, Lewis RE, et al. Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989–2003). Haematologica. 2006;91:986–9.

    PubMed  Google Scholar 

  4. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408–15. doi:10.1056/NEJMoa020191.

    Article  PubMed  CAS  Google Scholar 

  5. Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis. 2003;36:1122–31. doi:10.1086/374557.

    Article  PubMed  CAS  Google Scholar 

  6. Powers JH, Dixon CA, Goldberger MJ. Voriconazole versus liposomal amphotericin B in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:289–90. doi:10.1056/NEJM200201243460414.

    Article  PubMed  Google Scholar 

  7. Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother. 2002;46:2546–53. doi:10.1128/AAC.46.8.2546-2553.2002.

    Article  PubMed  CAS  Google Scholar 

  8. Dodds Ashley ESLR, Lewis JS, Martin C, Andes D. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006;43:28–39. doi:10.1086/504492.

    Article  Google Scholar 

  9. Geist MJ, Egerer G, Burhenne J, Mikus G. Safety of voriconazole in a patient with CYP2C9*2/CYP2C9*2 genotype. Antimicrob Agents Chemother. 2006;50:3227–8. doi:10.1128/AAC.00551-06.

    Article  PubMed  CAS  Google Scholar 

  10. Murayama N, Imai N, Nakane T, Shimizu M, Yamazaki H. Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes. Biochem Pharmacol. 2007;73:2020–6. doi:10.1016/j.bcp.2007.03.012.

    Article  PubMed  CAS  Google Scholar 

  11. Shimizu T, Ochiai H, Asell F, et al. Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19. Drug Metab Pharmacokinet. 2003;18:48–70. doi:10.2133/dmpk.18.48.

    Article  PubMed  CAS  Google Scholar 

  12. Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother. 2006;50:1570–2. doi:10.1128/AAC.50.4.1570-1572.2006.

    Article  PubMed  CAS  Google Scholar 

  13. 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;46:201–11. doi:10.1086/524669.

    Article  PubMed  CAS  Google Scholar 

  14. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007;25:571–8. doi:10.1200/JCO.2006.08.2305.

    Article  PubMed  Google Scholar 

  15. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46:1813–21. doi:10.1086/588660.

    Article  PubMed  Google Scholar 

  16. Kawazu M, Kanda Y, Nannya Y, et al. Prospective comparison of the diagnostic potential of real-time PCR, double-sandwich enzyme-linked immunosorbent assay for galactomannan, and a (1→3)-beta-d-glucan test in weekly screening for invasive aspergillosis in patients with hematological disorders. J Clin Microbiol. 2004;42:2733–41. doi:10.1128/JCM.42.6.2733-2741.2004.

    Article  PubMed  CAS  Google Scholar 

  17. Marr KA, Balajee SA, McLaughlin L, Tabouret M, Bentsen C, Walsh TJ. Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. J Infect Dis. 2004;190:641–9. doi:10.1086/422009.

    Article  PubMed  CAS  Google Scholar 

  18. Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis. 2007;44:373–9. doi:10.1086/509917.

    Article  PubMed  Google Scholar 

  19. Pascual A, Nieth V, Calandra T, et al. Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods. Antimicrob Agents Chemother. 2007;51:137–43. doi:10.1128/AAC.00957-06.

    Article  PubMed  CAS  Google Scholar 

  20. Almyroudis NG, Kontoyiannis DP, Sepkowitz KA, DePauw BE, Walsh TJ, Segal BH. Issues related to the design and interpretation of clinical trials of salvage therapy for invasive mold infection. Clin Infect Dis. 2006;43:1449–55. doi:10.1086/508455.

    Article  PubMed  Google Scholar 

  21. National Cancer institute. Serious adverse events definitions. In Edition National Cancer Institute 2006.

  22. Nivoix Y, Leveque D, Herbrecht R, Koffel JC, Beretz L, Ubeaud-Sequier G. The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet. 2008;47:779–92. doi:10.2165/0003088-200847120-00003.

    Article  PubMed  CAS  Google Scholar 

  23. Perea JR, Diaz De Rada BS, Quetglas EG, Juarez MJ. Oral versus intravenous therapy in the treatment of systemic mycosis. Clin Microbiol Infect. 2004;10(Suppl 1):96–106. doi:10.1111/j.1470-9465.2004.00846.x.

    Article  PubMed  Google Scholar 

  24. Caillot D, Couaillier JF, Bernard A, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol. 2001;19:253–9.

    PubMed  CAS  Google Scholar 

  25. Miceli MH, Maertens J, Buve K, et al. Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: Proof of principle, description, and clinical and research implications. Cancer. 2007;110:112–20. doi:10.1002/cncr.22738.

    Article  PubMed  Google Scholar 

  26. Obayashi T, Yoshida M, Tamura H, Aketagawa J, Tanaka S, Kawai T. Determination of plasma (1→3)-beta-d-glucan: a new diagnostic aid to deep mycosis. J Med Vet Mycol. 1992;30:275–80. doi:10.1080/02681219280000361.

    Article  PubMed  CAS  Google Scholar 

  27. Mennink-Kersten MA, Warris A, Verweij PE. 1,3-beta-d-glucan in patients receiving intravenous amoxicillin-clavulanic acid. N Engl J Med. 2006;354:2834–5. doi:10.1056/NEJMc053340.

    Article  PubMed  CAS  Google Scholar 

  28. Sulahian A, Touratier S, Ribaud P. False positive test for aspergillus antigenemia related to concomitant administration of piperacillin and tazobactam. N Engl J Med. 2003;349:2366–7. doi:10.1056/NEJM200312113492424.

    Article  PubMed  CAS  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;136:739–42.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We appreciate agency of Pfizer Japan Inc. and TSL Inc. for measuring voriconazole concentrations. We declare that we have no competing interests.

Conflict of interest statement

The authors do not have any conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Koki Ueda, Yasuhito Nannya, Akira Hangaishi, Tsuyoshi Takahashi, Yoichi Imai & Mineo Kurokawa

  2. Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan

    Keiki Kumano & Mineo Kurokawa

Authors
  1. Koki Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuhito Nannya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keiki Kumano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akira Hangaishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsuyoshi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoichi Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mineo Kurokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mineo Kurokawa.

About this article

Cite this article

Ueda, K., Nannya, Y., Kumano, K. 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 89, 592–599 (2009). https://doi.org/10.1007/s12185-009-0296-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-009-0296-3

Keywords

Search

Navigation