Recent Developments in Inhaled Triazoles Against Invasive Pulmonary Aspergillosis

Abstract

Invasive pulmonary aspergillosis (IPA) is a fungal infection that is seen with particular frequency in immunocompromised patients, and associated with high rates of mortality. To combat or prevent IPA, triazoles such as voriconazole or itraconazole and posaconazole have become accepted as first- and second-line therapy, respectively. However, triazoles are associated with issues of oral bioavailability, high liver metabolism, and/or drug–drug interactions, increasing the variability of systemic concentrations. As a way to overcome these issues, inhalation appears to be a promising route for delivery of triazoles for prophylactic or curative therapy in IPA. Indeed, pulmonary drug delivery drastically increases the drug in situ while decreasing the systemic exposure, thereby limiting drug metabolization, side effects, and drug–drug interactions. The development of triazoles for inhalation has focused on voriconazole and itraconazole, drugs which are both highly permeable but with significant different solubility. In this review, we describe the most advanced and promising pharmaceutical developments for voriconazole and itraconazole.

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

Fig. 1

Abbreviations

AI90H:

amorphous itraconazole with Phospholipon® 90H

AI:

amorphous itraconazole

AIN:

amorphous itraconazole nanoparticle-based aggregates

AIP1:

itraconazole nanoparticle-based aggregates with polysorbate 20

AIP2:

itraconazole nanoparticle-based aggregates with polysorbate 80 and Poloxamer 407

AmphB-deox:

amphotericin B deoxycholate

AUC:

area under the curve

Cmax :

maximum peak concentration

CI:

crystalline itraconazole

CIN:

crystalline itraconazole nanoparticles

CIP:

crystalline itraconazole nanoparticle-based aggregates

dae:

aerodynamic diameter

DPI:

dry powder inhaler

FPF:

fine particle fraction

HPβCD:

hydroxypropyl -β-cyclodextrin

ICD:

amorphous itraconazole-based inclusion complex with HPβCD

IPA:

invasive pulmonary aspergillosis

IPEC:

International Pharmaceutical Excipients Council

ITZ:

itraconazole

MIC:

minimum inhibitory concentration

MMAD:

median mass aerodynamic diameter

PEG:

polyethylene glycol

PLGA:

poly(lactide-co-glycolide)

Seq:

saturation solubility equilibrium

SeβCD:

sulfobutyl ether-β-cyclodextrin

t1/2 :

terminal half-life

VCZ:

voriconazole

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.

    Maschmeyer G, Jaas A, Cornely OA. Invasive Aspergillosis—epidemiology, diagnosis and management in immunocompromised patients. Drugs. 2007;67(11):1567–601.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Thompson GR, Patterson T. Pulmonary aspergillosis. Semin Respir Crit Care Med. 2008;29:103–10.

    PubMed  Article  Google Scholar 

  3. 3.

    Lass-Flörl C. Triazole antifungal agents in invasive fungal infections, a comparative review. Drugs. 2011;71(18):2405–19.

    PubMed  Article  Google Scholar 

  4. 4.

    Díaz Sánchez C, López VA. Pulmonary Aspergillosis. Arch Bronconeumol. 2004;40(3):114–22.

    PubMed  Article  Google Scholar 

  5. 5.

    Morris G, Kokki MH, Anderson K, Richardson MD. Sampling of Aspergillus spores in air. J Hosp Infect. 2000;44:81–92.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Latgé JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev. 1999;12(2):310–50.

    PubMed Central  PubMed  Google Scholar 

  7. 7.

    Dagenais TRT, Keller NP. Pathogenesis of Aspergillus fumigatus in invasive aspergillosis. Clin Microbiol Rev. 2009;22:447–65.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. 8.

    McConville JT, Wiederhold NP. Invasive pulmonary aspergillosis: therapeutic and prophylactic strategies. In: Williams III RO, Taft DR, McConville JT, editors. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes, Informa Healthcare, vol. 172. 2008. p. 53–80.

    Google Scholar 

  9. 9.

    Hasenberg M et al. Phagocyte responses towards Aspergillus fumigatus. Int J Med Microbiol. 2011;301:436–44.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest J. 2002;121(6):1988–99.

    Article  Google Scholar 

  11. 11.

    Amchentsev A, Kurugundla N, Saleh AG. Aspergillus-related lung disease. Respir Med CME. 2008;1:205–15.

    Article  Google Scholar 

  12. 12.

    Stevens DA et al. Practice guidelines for diseases caused by Aspergillus. Clin Infect Dis. 2000;30:696–709.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Sheppard DC. Molecular mechanism of Aspergillus fumigatus adherence to ghost constituents. Curr Opin Microbiol. 2011;14:375–9.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  14. 14.

    Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis: State of the art. Am J Respir Crit Care Med. 2006;173:707–17.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Traunmüller F et al. Efficacy and safety of current drug therapies for invasive aspergillosis. Pharmacology. 2011;88:213–24.

    PubMed  Article  Google Scholar 

  16. 16.

    Walsh TJ et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–60.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Herbrecht R et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408–15.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Yang W, Wiederhold NP, Williams RO. Drug delivery strategies for improved azole antifungal action. Expert Opin Drug Deliv. 2008;5(11):199–1216.

    Article  Google Scholar 

  19. 19.

    Perfect JR, Dodds Ashley E, Drew R. Design of aerosolized amphotericin B formulation for prophylaxis trials among lung transplant recipients. Clin Infect Dis. 2004;39:207–10.

    Article  Google Scholar 

  20. 20.

    Onoue S, Misaka S, Kawabata Y, Yamada S. New treatments for chronic obstructive pulmonary disease and viable formulation/device options for inhalation therapy. Expert Opin Drug Deliv. 2009;6:793–811.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Ibrahim BM, Tsifansky MD, Yang Y, Yeo Y. Challenges and advances in the development of inhalable drug formulations for cystic fibrosis lung disease. Expert Opin Drug Deliv. 2011;8:451–66.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Sears MR, Lotvall J. Past, present and future beta-2-adrenoreceptor agonist in asthma management. Respir Med. 2005;99:152–70.

    PubMed  Article  Google Scholar 

  23. 23.

    Smyth HDC, Saleem I, Donovan M, Verschraegen CF. Pulmonary delivery of anti-cancer agents. In: Williams III RO, Taft DR, McConville JT, editors. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes, Informa Healthcare, vol. 172. 2008. p. 81–112.

    Google Scholar 

  24. 24.

    Depreter F, Pilcer G, Amighi K. Inhaled proteins: challenges and perspectives. Int J Pharm. 2013;447:251–80.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Carvalho TC, Peters JI, Williams III RO. Influence of particle size on regional lung deposition—What evidence is there? Int J Pharm. 2011;406:1–10.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Hofmann W. Modelling inhaled particle deposition in the human lung—a review. J Aerosol Sci. 2011;42:693–724.

    CAS  Article  Google Scholar 

  27. 27.

    El-Sherbiny IM, Villanueva DG, Herrera D, Smyth HDC. Overcoming lung clearance mechanisms for controlled release drug delivery. In: Smyth HDC, Hickey AJ editors. Controlled Pulmonary Drug Delivery. Springer; 2011. pp. 101–126.

  28. 28.

    Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. J Clin Pharmacol. 2003;56:588–99.

    CAS  Article  Google Scholar 

  29. 29.

    O’Donnel P, Smyth HDC. Macro- and microstructure of the airways fro drug delivery. In: Smyth HDC, Hickey AJ editors. Controlled Pulmonary Drug Delivery. Springer; 2011. pp. 1–19.

  30. 30.

    Evans M. C, Koo JS. Airway mucus: the good, the bad, the sticky. Pharmacol Ther. 2009;121:332–48.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Harmsen AG, Muggenburg BA, Snipes MB, Bice DE. The role of macrophages in particle translocation from lungs to lymph nodes. Science. 1985;230:1277–80.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Wang YB, Watts AB, Peters JI, Williams III RO. The impact of pulmonary disease on the fate of inhaled medicines—a review. Int J Pharm. 2014;461:112–28.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Chono S, Tanino T, Seki T, Morimoto K. Influence of particle size on drug delivery to rat alveolar macrophages following pulmonary administration of ciprofloxacin incorporated to liposomes. J Drug Target. 2006;14:557–66.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Groneberg DA, Witt C, Wagner U, Chung KF, Fischer A. Fundamentals of pulmonary drug delivery. Respir Med. 2003;97:382–7.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale and clinical applications, existing and potential. Int J Nanomedicine. 2006;1(3):297–315.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. 36.

    Olsson B, Bondesson E, Borgström L, et al. Pulmonary drug metabolism, clearance and absorption. In: Smyth HDC, Hickey AJ editors. Controlled Pulmonary Drug Delivery. Springer; 2011. pp. 36–50.

  37. 37.

    Wiedmann TS, Bhatia R, Wattenberg LW. Drug solubilisation in lung surfactant. J Control Release. 2000;65:43–7.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Patton JS. Mechanism of macromolecule absorption by the lungs. Adv Drug Deliv Rev. 1996;19:3–36.

    CAS  Article  Google Scholar 

  39. 39.

    Patton JS, Brain JD, Davies LA, et al. The particle has landed—characterizing the fate of inhaled pharmaceuticals. J Aerosol Med Pulm Drug Deliv. 2010;23(2):71–87.

    Google Scholar 

  40. 40.

    Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392:1–19.

    CAS  PubMed  Article  Google Scholar 

  41. 41.•

    Williams HD et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65(1):315–499. Performed an overview of different strategies for poorly water-soluble drug.

    PubMed  Article  Google Scholar 

  42. 42.

    Tolman JA, Williams III RO. Advances in the pulmonary delivery of poorly water-soluble drugs: influence of solubilisation on pharmacokinetic properties. Drug Dev Ind Pharm. 2010;36(1):1–30.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Ruge CA, Kirch J, Lehr CM. Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges. Lancet Respir Med. 2013;1:402–13.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    US Food and Drug Administration. 2014. http://www.accessdata.fda.gov/scripts/fcn/fcnNavigation.cfm?rpt=scogsListing&displayAll=true. Accessed June 2014.

  45. 45.

    Buggins TR, Dickinson PA, Taylor G. The effects of pharmaceutical excipients on drug deposition. Adv Drug Deliv Rev. 2007;59:1482–503.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    US Food and Drug Administration. 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073395.pdf. Accessed June 2014.

  47. 47.

    Baldrick P. Pharmaceutical excipient development: the need for preclinical guidance. Regul Toxicol Pharmacol. 2000;32:210–8.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Baldrick P. Pharmaceutical excipient development: a preclinical challenge. In: Katdare A, Chaubal MV. Excipient Development for Pharmaceutical Biotechnology and Drug Delivery System. Informa Healthcare; 2006. pp. 15–36.

  49. 49.

    Baldrick P. The safety of chitosan as a pharmaceutical excipient. Regul Toxicol Pharmacol. 2010;56:290–9.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Islam N, Gladki E. Dry powder inhalers (DPIs)—a review of device reliability and innovation. Int J Pharm. 2008;360:1–11.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: evidence based guidelines. Chest. 2005;127:335–71.

    PubMed  Article  Google Scholar 

  52. 52.

    Dolovich MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. Lancet. 2011;377:1032–45.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Tolman JA et al. Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution. Eur J Pharm Biopharm. 2009;72:199–205.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Beinborn NA, Du J, Wiederhold NP, Smyth HDC, Williams III RO. Dry powder insufflation of crystalline and amorphous voriconazole formulations produced by thin film freezing to mice. Eur J Pharm Biopharm. 2012;81(3):600–8.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Sinha B, Mukherjee B, Pattnaik G. Poly-lactide-co-glycolide nanoparticles containing voriconazole for pulmonary delivery: in vitro and in vivo study. Nanomedicine. 2013;9:94–104.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    McConville JT et al. Targeted high lung concentration of itraconazole using nebulized dispersions in a murine model. Pharm Res. 2006;23(5):901–11.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Vaughn JM et al. Murine airway histology and intracellular uptake of inhaled amorphous itraconazole. Int J Pharm. 2007;38:219–24.

    Article  Google Scholar 

  58. 58.

    Yang W et al. High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers. Int J Pharm. 2007;361:177–88.

    Article  Google Scholar 

  59. 59.

    Yang W et al. In vitro characterization and pharmacokinetics in mice following pulmonary delivery of itraconazole as cyclodextrin solubilized solution. Eur J Pharm Sci. 2010;39:336–47.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Yang W, Johnston KP, Williams III RO. Comparison of bioavailability of amorphous versus crystalline itraconazole nanoparticles via pulmonary administration in rats. Eur J Pharm Biopharm. 2010;75:33–41.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Duret C, Wauthoz N, Sebti T, Vanderbist F, Amighi K. Solid dispersion of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties. Int J Pharm. 2012;428:103–13.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Duret C, Wauthoz N, Sebti T, Vanderbist F, Amighi K. New respirable and fast dissolving itraconazole dry powder composition for the treatment of invasive pulmonary aspergillosis. Pharm Res. 2012;29:2845–59.

    CAS  PubMed  Article  Google Scholar 

  63. 63.•

    Duret C et al. Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention. Eur J Pharm Biopharm. 2014;86:46–54. Study demonstrating the various steps of the characterization of a formulation intended to be administered by the pulmonary route from in vitro point of view to pharmacokinetic study on mice.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Duret C, Wauthoz N, Sebti T, Vanderbist F, Amighi K. New inhalation-optimized itraconazole nanoparticle-based dry powders fro the treatment of invasive pulmonary aspergillosis. Int J Nanomedicine. 2012;7:5475–89.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  65. 65.

    Rundfeldt C, Steckel H, Scherliess H, Wyska E, Wlaz P. Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis. Eur J Pharm Biopharm. 2013;83:44–53.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Pardeike J et al. Development of an itraconazole-loaded nanostructured lipid carrier (NLC) formulation for pulmonary application. Int J Pharm. 2011;419:329–38.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Moazeni E et al. Preparation and evaluation of inhalable itraconazole chitosan based polymeric micelles. Daru. 2012;20:85.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  68. 68.

    Jafarinejad S et al. Development of chitosan-based nanoparticles for pulmonary delivery of itraconazole as dry powder formulation. Powder Technol. 2012;222:65–70.

    CAS  Article  Google Scholar 

  69. 69.

    Tolman JA et al. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2009;53(6):2613–5.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  70. 70.

    Vaughn JM et al. Single dose and multiple dose studies of itraconazole nanoparticles. Eur J Pharm Biopharm. 2006;63:95–102.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Alvarez CA et al. Aerosolized nanostructured itraconazole as prophylaxis against invasive pulmonary aspergillosis. J Infect. 2007;55:68–74.

    PubMed  Article  Google Scholar 

  72. 72.

    Hoeben BJ et al. In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2006;50(4):1552–4.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  73. 73.

    Duret C, Wauthoz N, Rosière R, Sebti T, Vanderbist F, Amighi K. Prophylactic efficacy of inhaled itraconazole-mannitol dried solid dispersion against invasive pulmonary aspergillosis. Europe: Respiratory drug delivery; 2013.

    Google Scholar 

  74. 74.

    US Food and Drug Administration. 2014. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm128219.htm. Accessed June 2014.

  75. 75.

    Goodwin ML, Drew RH. Antifungal serum concentration monitoring: an update. J Antimicrob Chemother. 2008;61:17–25.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Pascual A et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46:201–11.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Vfend® characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000387/WC500049756.pdf. Accessed June 2014.

  78. 78.

    US Food and Drug Administration. 2014. http://www.accessdata.fda.gov/scripts/cder/iig/index.Cfm. Accessed June 2014.

  79. 79.

    O’Neil MJ. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 14th ed. New Jersey: Merck; 2006.

    Google Scholar 

  80. 80.

    Sporanox® characteristics. bijsluiters.fagg-afmps.be/DownloadLeafletServlet?id=123908. Accessed June 2014.

  81. 81.

    Prentice AG, Glasmacher A. Making sense of itraconazole pharmacokinetics. J Antimicrob Chemother. 2005;56:17–22.

    Article  Google Scholar 

  82. 82.

    De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs. 2001;61:27–37.

    PubMed  Article  Google Scholar 

  83. 83.

    Wauthoz N, Amighi K. Phospholipids in pulmonary drug delivery. Eur J Lipid Sci Technol. 2014. doi:10.1002/ejlt.201300368.

    Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. PO Gubbins of the University of Missouri–Kansas City for his review of the manuscript.

Compliance with Ethics Guidelines

Conflict of Interest

R. Merlos received a PhD grant from "Région Wallonne" for a subcontracting project with Galephar Pharmaceutical and Université Libre de Bruxelles.

K. Amighi and N. Wauthoz both declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Disclaimer

The findings and conclusions in this report are those of the author(s).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Nathalie Wauthoz.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Merlos, R., Amighi, K. & Wauthoz, N. Recent Developments in Inhaled Triazoles Against Invasive Pulmonary Aspergillosis. Curr Fungal Infect Rep 8, 331–342 (2014). https://doi.org/10.1007/s12281-014-0199-5

Download citation

Keywords

  • Aerosol
  • Antifungal
  • Aspergillosis
  • Fungal infection
  • Pulmonary delivery
  • Dry powder inhaler
  • Dry powder for inhalation
  • Nebulizer
  • Nebulization
  • Cyclodextrin
  • Nanoparticle
  • Solid dispersion
  • Controlled-release drug delivery