Skip to main content

Advertisement

SpringerLink
Log in

Effect of itraconazole on the concentrations of tacrolimus and cyclosporine in the blood of patients receiving allogeneic hematopoietic stem cell transplants

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to investigate the interactions of itraconazole (ITCZ) with orally administered calcineurin inhibitors (CNIs) in Japanese allogeneic hematopoietic stem cell transplant (HSCT) recipients.

Methods

Sixteen HSCT patients (8 patients each receiving tacrolimus or cyclosporine) were enrolled. An ITCZ oral solution was administered from day 30 after the initiation of ITCZ administration as a loading dose. Before the co-administration of ITCZ and CNI and 1 week daily thereafter, whole blood ITCZ and CNI (tacrolimus or cyclosporine) concentrations were measured in samples taken just before (C0h) and 2 h (C2h) after CNI administration.

Results

The median dose-adjusted C0h values of tacrolimus and cyclosporine on day 7 after the start of ITCZ co-administration were 5.6- and 2.7-fold higher, respectively, than the corresponding values obtained before the initiation of ITCZ treatment. On day 7 after ITCZ treatment, the mean single dosages of tacrolimus and cyclosporine were reduced to 33.7 and 66.5 % of the dosages before ITCZ co-administration, respectively, to adjust the CNI target concentration. Although ITCZ co-administration did not alter the dose-adjusted C0h values of tacrolimus in a patient with a CYP3A5*1/*1 allele, it did change this value of tacrolimus in patients with CYP3A5*3 alleles. However, in patients receiving cyclosporine, no such tendency was observed.

Conclusion

The magnitude of the interaction between orally administered tacrolimus and ITCZ was significantly greater than that between cyclosporine and ITCZ. Prospective analysis of the CYP3A5 polymorphism may be important to ensure safe and reliable immunosuppressive therapy with tacrolimus in patients treated with ITCZ.

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. Staatz CE, Tett SE (2004) Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 43(10):623–653

    Article  PubMed  CAS  Google Scholar 

  2. Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, Weimar W, van Gelder T (2003) Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 74(3):245–254. doi:10.1016/S0009-9236(03)00168-1

    Article  PubMed  CAS  Google Scholar 

  3. Roy JN, Barama A, Poirier C, Vinet B, Roger M (2006) Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients. Pharmacogenet Genom 16(9):659–665. doi:10.1097/01.fpc.0000220571.20961.dd

    Article  CAS  Google Scholar 

  4. Hesselink DA, van Gelder T, van Schaik RH (2005) The pharmacogenetics of calcineurin inhibitors: one step closer toward individualized immunosuppression? Pharmacogenomics 6(4):323–337. doi:10.1517/14622416.6.4.323

    Article  PubMed  CAS  Google Scholar 

  5. Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, Blumer JL, Leitz GJ, Territo MC (2003) Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med 138(9):705–713

    Article  PubMed  CAS  Google Scholar 

  6. Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA, Nichols WG, Musher B, Corey L (2004) Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 103(4):1527–1533. doi:10.1182/blood-2003-08-2644

    Article  PubMed  CAS  Google Scholar 

  7. Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000) Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 38(2):111–180

    Article  PubMed  CAS  Google Scholar 

  8. Niwa T, Shiraga T, Takagi A (2005) Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull 28(9):1805–1808

    Article  PubMed  CAS  Google Scholar 

  9. Koks CH, Meenhorst PL, Bult A, Beijnen JH (2002) Itraconazole solution: summary of pharmacokinetic features and review of activity in the treatment of fluconazole-resistant oral candidosis in HIV-infected persons. Pharmacol Res 46(2):195–201

    Article  PubMed  CAS  Google Scholar 

  10. Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE (2004) Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab Dispos: Biol Fate Chem 32(10):1121–1131. doi:10.1124/dmd.104.000315

    Article  CAS  Google Scholar 

  11. Buchkowsky SS, Partovi N, Ensom MH (2005) Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients. Ther Drug Monit 27(3):322–333

    Article  PubMed  CAS  Google Scholar 

  12. Varhe A, Olkkola KT, Neuvonen PJ (1994) Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 56(6 Pt 1):601–607

    Article  PubMed  CAS  Google Scholar 

  13. Jalava KM, Olkkola KT, Neuvonen PJ (1997) Itraconazole greatly increases plasma concentrations and effects of felodipine. Clin Pharmacol Ther 61(4):410–415. doi:10.1016/S0009-9236(97)90191-0

    Article  PubMed  CAS  Google Scholar 

  14. Huang W, Lin YS, McConn DJ 2nd, Calamia JC, Totah RA, Isoherranen N, Glodowski M, Thummel KE (2004) Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos: Biol Fate Chem 32(12):1434–1445. doi:10.1124/dmd.104.001313

    Article  CAS  Google Scholar 

  15. Yamazaki H, Nakamoto M, Shimizu M, Murayama N, Niwa T (2010) Potential impact of cytochrome P450 3A5 in human liver on drug interactions with triazoles. Br J Clin Pharmacol 69(6):593–597. doi:10.1111/j.1365-2125.2010.03656.x

    Article  PubMed  CAS  Google Scholar 

  16. Hustert E, Haberl M, Burk O, Wolbold R, He YQ, Klein K, Nuessler AC, Neuhaus P, Klattig J, Eiselt R, Koch I, Zibat A, Brockmoller J, Halpert JR, Zanger UM, Wojnowski L (2001) The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 11(9):773–779

    Article  PubMed  CAS  Google Scholar 

  17. Nara M, Takahashi N, Miura M, Saitoh H, Kagaya H, Sawada K (2010) Effect of oral itraconazole on the pharmacokinetics of tacrolimus in a hematopoietic stem cell transplant recipient with CYP3A5*3/*3. Am J Hematol 85(8):634–635. doi:10.1002/ajh.21759

    Article  PubMed  Google Scholar 

  18. Wallemacq P, Maine GT, Berg K, Rosiere T, Marquet P, Aimo G, Mengozzi G, Young J, Wonigeit K, Kretschmer R, Wermuth B, Schmid RW (2010) Multisite analytical evaluation of the Abbott ARCHITECT cyclosporine assay. Ther Drug Monit 32(2):145–151. doi:10.1097/FTD.0b013e3181d46386

    PubMed  CAS  Google Scholar 

  19. Amann S, Parker TS, Levine DM (2009) Evaluation of 2 immunoassays for monitoring low blood levels of tacrolimus. Ther Drug Monit 31(2):273–276. doi:10.1097/FTD.0b013e318196dfed

    Article  PubMed  CAS  Google Scholar 

  20. Miura M, Takahashi N, Nara M, Fujishima N, Kagaya H, Kameoka Y, Saitoh H, Tagawa H, Sawada K (2010) A simple, sensitive high-performance liquid chromatography-ultraviolet method for the quantification of concentration and steady-state pharmacokinetics of itraconazole and hydroxyitraconazole. Ann Clin Biochem 47(Pt 5):432–439. doi:10.1258/acb.2010.010029

    Article  PubMed  CAS  Google Scholar 

  21. Fukuen S, Fukuda T, Maune H, Ikenaga Y, Yamamoto I, Inaba T, Azuma J (2002) Novel detection assay by PCR-RFLP and frequency of the CYP3A5 SNPs, CYP3A5*3 and *6, in a Japanese population. Pharmacogenetics 12(4):331–334

    Article  PubMed  CAS  Google Scholar 

  22. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15(6):825–828

    PubMed  CAS  Google Scholar 

  23. Santoro A, Felipe CR, Tedesco-Silva H, Medina-Pestana JO, Struchiner CJ, Ojopi EB, Suarez-Kurtz G (2011) Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients. Pharmacogenomics 12(9):1293–1303. doi:10.2217/pgs.11.70

    Article  PubMed  CAS  Google Scholar 

  24. Anglicheau D, Legendre C, Beaune P, Thervet E (2007) Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics 8(7):835–849. doi:10.2217/14622416.8.7.835

    Article  PubMed  CAS  Google Scholar 

  25. Leather H, Boyette RM, Tian L, Wingard JR (2006) Pharmacokinetic evaluation of the drug interaction between intravenous itraconazole and intravenous tacrolimus or intravenous cyclosporin A in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant 12(3):325–334. doi:10.1016/j.bbmt.2005.10.022

    Article  PubMed  CAS  Google Scholar 

  26. Uesugi M, Masuda S, Katsura T, Oike F, Takada Y, Inui K (2006) Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients. Pharmacogenet Genomics 16(2):119–127

    Article  PubMed  CAS  Google Scholar 

  27. Templeton IE, Thummel KE, Kharasch ED, Kunze KL, Hoffer C, Nelson WL, Isoherranen N (2008) Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo. Clin Pharmacol Ther 83(1):77–85. doi:10.1038/sj.clpt.6100230

    Article  PubMed  CAS  Google Scholar 

  28. Amundsen R, Asberg A, Ohm IK, Christensen H (2012) Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro. Drug Metab Dispos: Biol Fate Chem 40(4):655–661. doi:10.1124/dmd.111.043018

    Article  CAS  Google Scholar 

  29. Keogh JP, Kunta JR (2006) Development, validation and utility of an in vitro technique for assessment of potential clinical drug-drug interactions involving P-glycoprotein. Eur J Pharm Sci 27(5):543–554. doi:10.1016/j.ejps.2005.11.011

    Article  PubMed  CAS  Google Scholar 

  30. Shon JH, Yoon YR, Hong WS, Nguyen PM, Lee SS, Choi YG, Cha IJ, Shin JG (2005) Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism. Clin Pharmacol Ther 78(2):191–201. doi:10.1016/j.clpt.2005.04.012

    Article  PubMed  CAS  Google Scholar 

  31. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84(21):7735–7738

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita City, Akita, 010-8543, Japan

    Miho Nara, Naoto Takahashi, Hirobumi Saitoh, Yoshihiro Kameoka, Hiroyuki Tagawa & Kenichi Sawada

  2. Department of Pharmacy, Akita University Hospital, Akita, Japan

    Masatomo Miura, Takenori Niioka & Hideaki Kagaya

  3. Division of Blood Transfusion, Akita University Hospital, Akita, Japan

    Naohito Fujishima

  4. Clinical Oncology Center, Akita University Hospital, Akita, Japan

    Makoto Hirokawa

Authors
  1. Miho Nara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoto Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masatomo Miura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takenori Niioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hideaki Kagaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naohito Fujishima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hirobumi Saitoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshihiro Kameoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroyuki Tagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Makoto Hirokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kenichi Sawada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naoto Takahashi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nara, M., Takahashi, N., Miura, M. et al. Effect of itraconazole on the concentrations of tacrolimus and cyclosporine in the blood of patients receiving allogeneic hematopoietic stem cell transplants. Eur J Clin Pharmacol 69, 1321–1329 (2013). https://doi.org/10.1007/s00228-013-1471-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-013-1471-2

Keywords

Search

Navigation