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Drug interaction between voriconazole and tacrolimus and its association with the bioavailability of oral voriconazole in recipients of allogeneic hematopoietic stem cell transplantation

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Abstract

In a previous study, we noted wide inter-individual variability in drug interactions between voriconazole and tacrolimus, but that analysis did not take into account the routes of administration. In the present study, we analyzed interactions between these two drugs when both agents were administered orally after allogeneic hematopoietic stem cell transplantation (HSCT); the effect of plasma voriconazole levels on the magnitude of the drug interaction was also examined. Twenty-five allogeneic HSCT recipients were evaluated. Trough concentrations of tacrolimus were measured prior to, and periodically for 7–10 days after, initiating voriconazole (400 mg/day) to determine the concentration/dose (C/D) ratio of tacrolimus. The median C/D ratio of tacrolimus increased significantly from 172.8 (range 28.6–1110.7) to 537.5 (range 127.8–1933.3) (ng/mL)/(mg/kg) (P < 0.01) following initiation of voriconazole; the median increase was 138.8 % (range −32.0 to 685.7 %). The plasma concentration of voriconazole did not correlate with the increase of the tacrolimus C/D ratio (ρ = 0.16, P = 0.44). These results indicate that oral voriconazole has a significant drug interaction with oral tacrolimus with a wide inter-individual variability, which cannot be explained by the bioavailability of voriconazole. Other possible mechanisms should be explored in future studies.

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References

  1. Dykewicz CA, Jaffe HW. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2006;6:670–2.

    Google Scholar 

  2. 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;34:909–17.

    Article  PubMed  Google Scholar 

  3. Kami M, Machida U, Okuzumi K, Matsumura T, Mori S, Hori A, et al. Effect of fluconazole prophylaxis on fungal blood cultures: an autopsy-based study involving 720 patients with haematological malignancy. Br J Haematol. 2002;117:40–6.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Jeu L, Piacenti FJ, Lyakhovetskiy AG, Fung HB. Voriconazole. Clin Ther. 2003;25:1321–81.

    Article  PubMed  CAS  Google Scholar 

  6. Herbrecht R, Fluckiger U, Gachot B, Ribaud P, Thiebaut A, Cordonnier C. Treatment of invasive Candida and invasive Aspergillus infections in adult haematological patients. Eur J Cancer Suppl. 2007;5:49–59.

    Article  CAS  Google Scholar 

  7. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–60.

    Article  PubMed  CAS  Google Scholar 

  8. Saad AH, DePestel DD, Carver PL. Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy. 2006;26:1730–44.

    Article  PubMed  CAS  Google Scholar 

  9. Romero AJ, Le Pogamp P, Nilsson LG, Wood N. Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther. 2002;71:226–34.

    Article  PubMed  CAS  Google Scholar 

  10. Wood N, Tank K, Allan R, Fielding A. Effect of voriconazole on the pharmacokinetics of tacrolimus. In: Program and Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, 22–25 September 2001 (abstract A-20). Washington DC: American Society of Microbiology; 2001.

  11. Inc Pfizer. Vfend (voriconazole) package insert. New York: Pfizer Inc.; 2010.

    Google Scholar 

  12. Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S. Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2009;44:371–4.

    Article  PubMed  CAS  Google Scholar 

  13. Lazarus HM, Blumer JL, Yanovich S, Schlamm H, Romero A. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol. 2002;42:395–402.

    Article  PubMed  CAS  Google Scholar 

  14. 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;35:509–13.

    Article  PubMed  CAS  Google Scholar 

  15. Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose PG, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother. 2006;50:1570–2.

    Article  PubMed  CAS  Google Scholar 

  16. Trifilio S, Pennick G, Pi J, Zook J, Golf M, Kaniecki K, et al. Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients. Cancer. 2007;109:1532–5.

    Article  PubMed  CAS  Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. Brüggemann RJ, Blijlevens NM, Burger DM, Franke B, Troke PF, Donnelly JP. Pharmacokinetics and safety of 14 days intravenous voriconazole in allogeneic haematopoietic stem cell transplant recipients. J Antimicrob Chemother. 2010;65:107–13.

    Article  PubMed  Google Scholar 

  19. Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S. Drug interaction between oral solution itraconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplantation recipients: an association with bioavailability of oral solution itraconazole. Int J Hematol. 2009;90:103–7.

    Article  PubMed  CAS  Google Scholar 

  20. Trifilio SM, Yarnold PR, Scheetz MH, Pi J, Pennick G, Mehta J. Serial plasma voriconazole concentrations after allogeneic hematopoietic stem cell transplantation. Antimicrob Agents Chemother. 2009;53:1793–6.

    Article  PubMed  CAS  Google Scholar 

  21. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38:41–57.

    Article  PubMed  CAS  Google Scholar 

  22. Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther. 2003;74:245–54.

    Article  PubMed  CAS  Google Scholar 

  23. Haufroid V, Mourad M, Van Kerckhove V, Wawrzyniak J, De Meyer M, Eddour DC, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 2004;14:147–54.

    Article  PubMed  CAS  Google Scholar 

  24. Onizuka M, Kunii N, Toyosaki M, Machida S, Ohgiya D, Ogawa Y, et al. Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients. Bone Marrow Transplant. 2010;46:1113–7. doi:10.1038/bmt.2010.273.

    Article  PubMed  Google Scholar 

  25. Lown KS, Kolars JC, Thummel KE, Barnett JL, Kunze KL, Wrighton SA, et al. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab Dispos. 1994;22:947–55.

    PubMed  CAS  Google Scholar 

  26. Ho RH, Kim RB. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther. 2005;78:260–77.

    Article  PubMed  CAS  Google Scholar 

  27. Nivoix Y, Levêque 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.

    Article  PubMed  CAS  Google Scholar 

  28. Purkins L, Wood N, Kleinermans D, Nichols D. Voriconazole does not affect the steady-state pharmacokinetics of digoxin. Br J Clin Pharmacol. 2003;56(Suppl 1):45–50.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by grants from the Japanese Ministry of Health, Labor, and Welfare.

Conflict of interest

All authors report the following funding sources which could have possible relevance to the work described here: Division of Hematology, Department of Medicine, Keio University School of Medicine has research funding from Pfizer Inc. and Astellas Pharma Inc.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Takehiko Mori, Jun Kato, Akiko Yamane, Masatoshi Sakurai, Sumiko Kohashi, Taku Kikuchi, Yukako Ono & Shinichiro Okamoto

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  1. Takehiko Mori
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  2. Jun Kato
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  3. Akiko Yamane
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  4. Masatoshi Sakurai
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  5. Sumiko Kohashi
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  6. Taku Kikuchi
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  7. Yukako Ono
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  8. Shinichiro Okamoto
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Correspondence to Takehiko Mori.

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Mori, T., Kato, J., Yamane, A. et al. Drug interaction between voriconazole and tacrolimus and its association with the bioavailability of oral voriconazole in recipients of allogeneic hematopoietic stem cell transplantation. Int J Hematol 95, 564–569 (2012). https://doi.org/10.1007/s12185-012-1057-2

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  • DOI: https://doi.org/10.1007/s12185-012-1057-2

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