Clinical Pharmacokinetics of Second-Generation Triazoles for the Treatment of Invasive Aspergillosis and Candidiasis

  • Zorica Jović
  • Slobodan M. JankovićEmail author
  • Dejana Ružić Zečević
  • Dragan Milovanović
  • Srđan Stefanović
  • Marko Folić
  • Jasmina Milovanović
  • Marina Kostić
Review Article


Second-generation triazoles were developed in response to the quest for more efficacious and safer therapeutic options for the treatment of severe systemic aspergillosis and candidiasis. These agents include voriconazole, posaconazole, isavuconazole, and ravuconazole. The aim of this review was to present and compare the pharmacokinetic characteristics of second-generation triazoles for the treatment of invasive aspergillosis and candidiasis, emphasizing their clinical implications. The MEDLINE, Scopus, EBSCO, Google Scholar, and SCIndeks databases were searched using advanced search options, including the names of second-generation triazoles and pharmacokinetic terms as keywords. The intravenous administration of voriconazole, posaconazole, and isavuconazole results in stable pharmacokinetics of these drugs, with mostly predictable variations influenced by common and usually known factors in routine clinical settings. The high oral bioavailability of isavuconazole and, to some extent, voriconazole makes them suitable for intravenous-to-oral switch strategies. Except for intravenous voriconazole (due to the accumulation of the toxic vehicle hydroxypropyl betadex), dose reduction of second-generation triazoles is not needed in patients with renal failure; patients with hepatic insufficiency require dose reduction only in advanced disease stages. The introduction of therapeutic drug monitoring could aid attempts to optimize the blood concentrations of triazoles and other drugs that are known to or that possibly interact, thus increasing treatment efficacy and safety. There is a need for new studies that are designed to provide useful data on second-generation triazole pharmacokinetics, particularly in special circumstances such as central nervous system and ocular infections, infections in newborns and infants, and in subjects with genetic polymorphisms of metabolizing enzymes.


Compliance with Ethical Standards

Conflict of interest

None of the authors has any conflict of interest in regard to the content of this manuscript.


This manuscript was partially financed by a grant (no. 175007) given by the Serbian Ministry of Education, Science, and Technology.


  1. 1.
    Kontoyiannis DP, Mantadakis E, Samonis G. Systemic mycoses in the immunocompromised host: an update in antifungal therapy. J Hosp Infect. 2003;53(4):243–58.CrossRefGoogle Scholar
  2. 2.
    Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012;4(165):165rv13.CrossRefGoogle Scholar
  3. 3.
    Denning DW, Hope WW. Therapy for fungal diseases: opportunities and priorities. Trends Microbiol. 2010;18(5):195–204.CrossRefGoogle Scholar
  4. 4.
    Lass-Florl C. Triazole antifungal agents in invasive fungal infections: a comparative review. Drugs. 2011;71(18):2405–19.CrossRefGoogle Scholar
  5. 5.
    Patterson TF, Thompson GR III, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):433–42.CrossRefGoogle Scholar
  6. 6.
    Torres HA, Hachem RY, Chemaly RF, Kontoyiannis DP, Raad II. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis. 2005;5(12):775–85.CrossRefGoogle Scholar
  7. 7.
    Rybak JM, Marx KR, Nishimoto AT, Rogers PD. Isavuconazole: pharmacology, pharmacodynamics, and current clinical experience with a new triazole antifungal agent. Pharmacotherapy. 2015;35(11):1037–51.CrossRefGoogle Scholar
  8. 8.
    Shirley M, Scott LJ. Isavuconazole: a review in invasive aspergillosis and mucormycosis. Drugs. 2016;76(17):1647–57.CrossRefGoogle Scholar
  9. 9.
    Cuenca-Estrella M, Gomez-Lopez A, Mellado E, Garcia-Effron G, Rodriguez-Tudela JL. In vitro activities of ravuconazole and four other antifungal agents against fluconazole-resistant or -susceptible clinical yeast isolates. Antimicrob Agents Chemother. 2004;48(8):3107–11.CrossRefGoogle Scholar
  10. 10.
    Scholz I, Oberwittler H, Riedel KD, et al. Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype. Br J Clin Pharmacol. 2009;68:906–15.CrossRefGoogle Scholar
  11. 11.
    Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother. 2009;53:24–34.CrossRefGoogle Scholar
  12. 12.
    Wilby KJ. A review of the clinical pharmacokinetics and pharmacodynamics of isavuconazole. Eur J Drug Metab Pharmacokinet. 2017. Scholar
  13. 13.
    Levêque D, Nivoix Y, Jehl F, Herbrecht R. Clinical pharmacokinetics of voriconazole. Int J Antimicrob Agents. 2006;27(4):274–84.CrossRefGoogle Scholar
  14. 14.
    European Medicines Agency. Vfend: summary of product characteristics. Cited 8 Mar 2018.
  15. 15.
    Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Infectious Diseases Society of America, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):e56–93.Google Scholar
  16. 16.
    Maertens JA. History of the development of azole derivatives. Clin Microbiol Infect. 2004;10(Suppl 1):1–10.CrossRefGoogle Scholar
  17. 17.
    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(8):2546–53.CrossRefGoogle Scholar
  18. 18.
    Purkins L, Wood N, Greenhalgh K, Allen MJ, Oliver SD. Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br J Clin Pharmacol. 2003;56(Suppl 1):10–6.CrossRefGoogle Scholar
  19. 19.
    Veringa A, Geling S, Span LFR, Vermeulen KM, Zijlstra JG, van derWerf TS, Kosterink JGW, Jan-Willem C, Alffenaar JWC. Bioavailability of voriconazole in hospitalised patients. Int J Antimicrob Agents. 2017;49(2):243–6.CrossRefGoogle Scholar
  20. 20.
    Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet. 2006;45(7):649–63.CrossRefGoogle Scholar
  21. 21.
    Purkins L, Wood N, Kleinermans D, Greenhalgh K, Nichols D. Effect of food on the pharmacokinetics of multiple-dose oral voriconazole. Br J Clin Pharmacol. 2003;56(Suppl 1):17–23.CrossRefGoogle Scholar
  22. 22.
    Kuo FI, Ensom MHH. Role of therapeutic drug monitoring of voriconazole in the treatment of invasive fungal infections. Can J Hosp Pharm. 2009;62(6):469–82.Google Scholar
  23. 23.
    Ikeda Y, Umemura K, Kondo K, Sekiguchi K, Miyoshi S, Nakashima M. Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status. Clin Pharmacol Ther. 2004;75(6):587–8.CrossRefGoogle Scholar
  24. 24.
    Dolton MJ, McLachlan AJ. Voriconazole pharmacokinetics and exposure–response relationships: assessing the links between exposure, efficacy and toxicity. Int J Antimicrob Agents. 2014;44(3):183–93.Google Scholar
  25. 25.
    Scholz I, Oberwittler H, Riedel KD, Burhenne J, Weiss J, Haefeli WE, Mikus G. Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype. Br J Clin Pharmacol. 2009;68(6):906–15.CrossRefGoogle Scholar
  26. 26.
    Driscoll TA, Yu LC, Frangoul H, Krance RA, Nemecek E, Blumer J, Arrieta A, Graham ML, Bradfield SM, Baruch A, Liu P. 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.CrossRefGoogle Scholar
  27. 27.
    Abel S, Allan R, Gandelman K, Tomaszewski K, Webb DJ, Wood ND. Pharmacokinetics, safety and tolerance of voriconazole in renally impaired subjects. Clin Drug Investig. 2008;28(7):409–20.CrossRefGoogle Scholar
  28. 28.
    Wang T, Xie J, Wang Y, Zheng X, Lei JE, Wang X, et al. Pharmacokinetic and pharmacodynamic properties of oral voriconazole in patients with invasive fungal infections. Pharmacotherapy. 2015;35(9):797–804.CrossRefGoogle Scholar
  29. 29.
    Huurneman LJ, Neely M, Veringa A, Pérez FD, Ramos-Martin V, Tissing WJ, et al. Pharmacodynamics of voriconazole in children: further steps along the path to true individualized therapy. Antimicrob Agents Chemother. 2016;60(4):2336–42.CrossRefGoogle Scholar
  30. 30.
    Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis. 2003;36(5):630–7.CrossRefGoogle Scholar
  31. 31.
    Sandherr M, Maschmeyer G. Pharmacology and metabolism of voriconazole and posaconazole in the treatment of invasive aspergillosis—review of the literature. Eur J Med Res. 2011;16(4):139–44.CrossRefGoogle Scholar
  32. 32.
    Qi F, Zhu L, Li N, Ge T, Xu G, Liao S. Influence of different proton pump inhibitors on the pharmacokinetics of voriconazole. Int J Antimicrob Agents. 2017;49(4):403–9.CrossRefGoogle Scholar
  33. 33.
    Purkins L, Wood N, Ghahramani P, Love ER, Eve MD, Fielding A. Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. BJCP. 2003;56(s1):37–44.Google Scholar
  34. 34.
    Allegra S, Fatiguso G, De Francia S, Favata F, Pirro E, Carcieri C, De Nicolò A, Cusato J, Di Perri G, D’Avolio A. Evaluation of posaconazole pharmacokinetics in adult patients with invasive fungal infection. Biomedicines. 2017;5(4):E66.Google Scholar
  35. 35.
    Petitcollin A, Crochette R, Tron C, Verdier MC, Boglione-Kerrien C, Vigneau C, Bellissant E, Lemaitre F. Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole. Drug Metab Pharmacokinet. 2016;31(5):389–93.CrossRefGoogle Scholar
  36. 36.
    Mellinghoff SC, Panse J, Alakel N, Behre G, Buchheidt D, Christopeit M, et al. Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Ann Hematol. 2018;97(2):197–207.Google Scholar
  37. 37.
    Eiden C, Meniane JC, Peyrière H, Eymard-Duvernay S, Le Falher G, Ceballos P, et al. Therapeutic drug monitoring of posaconazole in hematology adults under posaconazole prophylaxis: influence of food intake. Eur J Clin Microbiol Infect Dis. 2012;31(2):161–7.CrossRefGoogle Scholar
  38. 38.
    Lipp HP. Clinical pharmacodynamics and pharmacokinetics of the antifungal extended-spectrum triazole posaconazole: an overview. Br J Clin Pharmacol. 2010;70(4):471–80.CrossRefGoogle Scholar
  39. 39.
    Krishna G, Moton A, Ma L, Medlock MM, McLeod J. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother. 2009;53(3):958–66.CrossRefGoogle Scholar
  40. 40.
    Dolton MJ, Brüggemann RJ, Burger DM, McLachlan AJ. Understanding variability in posaconazole exposure using an integrated population pharmacokinetic analysis. Antimicrob Agents Chemother. 2014;58(11):6879–85.CrossRefGoogle Scholar
  41. 41.
    Alffenaar JW, van Assen S, van der Werf TS, Kosterink JG, Uges DR. Omeprazole significantly reduces posaconazole serum trough level. Clin Infect Dis. 2009;48(6):839.CrossRefGoogle Scholar
  42. 42.
    Vehreschild JJ, Müller C, Farowski F, Vehreschild MJ, Cornely OA, Fuhr U, et al. Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome. Eur J Clin Pharmacol. 2012;68(6):987–95.CrossRefGoogle Scholar
  43. 43.
    Kohl V, Müller C, Cornely OA, Abduljalil K, Fuhr U, Vehreschild JJ, et al. Factors influencing pharmacokinetics of prophylactic posaconazole in patients undergoing allogeneic stem cell transplantation. Antimicrob Agents Chemother. 2010;54(1):207–12.CrossRefGoogle Scholar
  44. 44.
    Krishna G, Martinho M, Chandrasekar P, Ullmann AJ, Patino H. Pharmacokinetics of oral posaconazole in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease. Pharmacotherapy. 2007;27(12):1627–36.CrossRefGoogle Scholar
  45. 45.
    Störzinger D, Borghorst S, Hofer S, Busch CJ, Lichtenstern C, Hempel G, et al. Plasma concentrations of posaconazole administered via nasogastric tube in patients in a surgical intensive care unit. Antimicrob Agents Chemother. 2012;56(8):4468–70.CrossRefGoogle Scholar
  46. 46.
    Sienkiewicz BM, Łapiński Ł, Wiela-Hojeńska A. Comparison of clinical pharmacology of voriconazole and posaconazole. Contemp Oncol (Pozn). 2016;20(5):365–73.Google Scholar
  47. 47.
    Leclerc E, Combarel D, Uzunov M, Leblond V, Funck-Brentano C, Zahr N. Prevention of invasive aspergillus fungal infections with the suspension and delayed-release tablet formulations of posaconazole in patients with haematologic malignancies. Sci Rep. 2018;8(1):1681.CrossRefGoogle Scholar
  48. 48.
    Guarascio AJ, Slain D. Review of the new delayed-release oral tablet and intravenous dosage forms of posaconazole. Pharmacotherapy. 2015;35(2):208–19.CrossRefGoogle Scholar
  49. 49.
    Kraft WK, Chang PS, van Iersel ML, Waskin H, Krishna G, Kersemaekers WM. Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects. Antimicrob Agents Chemother. 2014;58(7):4020–5.CrossRefGoogle Scholar
  50. 50.
    Krishna G, Ma L, Martinho M, Preston RA, O’Mara E. A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers. J Antimicrob Chemother. 2012;67(11):2725–30.CrossRefGoogle Scholar
  51. 51.
    Belling M, Kanate AS, Shillingburg A, Lu X, Wen S, Shah N, et al. Evaluation of serum posaconazole concentrations in patients with hematological malignancies receiving posaconazole suspension compared to the delayed-release tablet formulation. Leuk Res Treat. 2017;2017:3460892.Google Scholar
  52. 52.
    Cornely OA, Robertson MN, Haider S, Grigg A, Geddes M, Aoun M, et al. Pharmacokinetics and safety results from the phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease. J Antimicrob Chemother. 2017;72(12):3406–13.CrossRefGoogle Scholar
  53. 53.
    Kersemaekers WM, van Iersel T, Nassander U, O’Mara E, Waskin H, Caceres M, et al. Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects. Antimicrob Agents Chemother. 2015;59(2):1246–51.CrossRefGoogle Scholar
  54. 54.
    McKeage K. Posaconazole: a review of the gastro-resistant tablet and intravenous solution in invasive fungal infections. Drugs. 2015;75(4):397–406.CrossRefGoogle Scholar
  55. 55.
    Yi WM, Schoeppler KE, Jaeger J, Mueller SW, MacLaren R, Fish DN, et al. Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study. Ann Clin Microbiol Antimicrob. 2017;16(1):60.CrossRefGoogle Scholar
  56. 56.
    Li J, Nguyen CT, Garcia-Diaz J. Role of new antifungal agents in the treatment of invasive fungal infections in transplant recipients: isavuconazole and new posaconazole formulations. J Fungi (Basel). 2015;1(3):345–66.CrossRefGoogle Scholar
  57. 57.
    Bellmann R, Smuszkiewicz P. Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients. Infection. 2017;45(6):737–79.CrossRefGoogle Scholar
  58. 58.
    Ullmann AJ, Cornely OA, Burchardt A, Hachem R, Kontoyiannis DP, Töpelt K, et al. Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection. Antimicrob Agents Chemother. 2006;50(2):658–66.CrossRefGoogle Scholar
  59. 59.
    Conte JE Jr, DeVoe C, Little E, Golden JA. Steady-state intrapulmonary pharmacokinetics and pharmacodynamics of posaconazole in lung transplant recipients. Antimicrob Agents Chemother. 2010;54(9):3609–13.CrossRefGoogle Scholar
  60. 60.
    Thakuria L, Packwood K, Firouzi A, Rogers P, Soresi S, Habibi-Parker K, et al. A pharmacokinetic analysis of posaconazole oral suspension in the serum and alveolar compartment of lung transplant recipients. Int J Antimicrob Agents. 2016;47(1):69–76.CrossRefGoogle Scholar
  61. 61.
    Rüping MJ, Albermann N, Ebinger F, Burckhardt I, Beisel C, Müller C, et al. Posaconazole concentrations in the central nervous system. J Antimicrob Chemother. 2008;62(6):1468–70.CrossRefGoogle Scholar
  62. 62.
    Reinwald M, Uharek L, Lampe D, Grobosch T, Thiel E, Schwartz S. Limited penetration of posaconazole into cerebrospinal fluid in an allogeneic stem cell recipient with invasive pulmonary aspergillosis. Bone Marrow Transplant. 2009;44(4):269–70.CrossRefGoogle Scholar
  63. 63.
    Blennow O, Eliasson E, Pettersson T, Pohanka A, Szakos A, El-Serafi I, et al. Posaconazole concentrations in human tissues after allogeneic stem cell transplantation. Antimicrob Agents Chemother. 2014;58(8):4941–3.CrossRefGoogle Scholar
  64. 64.
    Farowski F, Cornely OA, Vehreschild JJ, Hartmann P, Bauer T, Steinbach A, et al. Intracellular concentrations of posaconazole in different compartments of peripheral blood. Antimicrob Agents Chemother. 2010;54(7):2928–31.CrossRefGoogle Scholar
  65. 65.
    Zhang H, Nguyen MH, Clancy CJ, Joshi R, Zhao W, Ensor C, et al. Pharmacokinetics of posaconazole suspension in lung transplant patients with and without cystic fibrosis. Antimicrob Agents Chemother. 2016;60(6):3558–62.CrossRefGoogle Scholar
  66. 66.
    Miceli MH, Perissinotti AJ, Kauffman CA, Couriel DR. Serum posaconazole levels among haematological cancer patients taking extended release tablets is affected by body weight and diarrhoea: single centre retrospective analysis. Mycoses. 2015;58(7):432–6.CrossRefGoogle Scholar
  67. 67.
    Ghosal A, Hapangama N, Yuan Y, Achanfuo-Yeboah J, Iannucci R, Chowdhury S, et al. Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil). Drug Metab Dispos. 2004;32(2):267–71.CrossRefGoogle Scholar
  68. 68.
    Krieter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R. Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agents Chemother. 2004;48(9):3543–51.Google Scholar
  69. 69.
    Krishna G, Ma L, Martinho M, O’Mara E. Single-dose phase I study to evaluate the pharmacokinetics of posaconazole in new tablet and capsule formulations relative to oral suspension. Antimicrob Agents Chemother. 2012;56(8):4196–201.CrossRefGoogle Scholar
  70. 70.
    Hachem RY, Langston AA, Graybill JR, Perfect JR, Pedicone LD, Patino H, et al. Posaconazole as salvage treatment of invasive fungal infections in patients with underlying renal impairment. J Antimicrob Chemother. 2008;62(6):1386–91.CrossRefGoogle Scholar
  71. 71.
    Morris AA, Mueller SW, Rower JE, Washburn T, Kiser TH. Evaluation of sulfobutylether-β-cyclodextrin exposure in a critically ill patient receiving intravenous posaconazole while undergoing continuous venovenous hemofiltration. Antimicrob Agents Chemother. 2015;59(10):6653–66.CrossRefGoogle Scholar
  72. 72.
    Moton A, Krishna G, Ma L, O’Mara E, Prasad P, McLeod J, et al. Pharmacokinetics of a single dose of the antifungal posaconazole as oral suspension in subjects with hepatic impairment. Curr Med Res Opin. 2010;26(1):1–7.CrossRefGoogle Scholar
  73. 73.
    McMahon J, Théorêt Y, Autmizguine J, Bittencourt H, Tapiéro B, Ovetchkine P. Posaconazole plasma monitoring in immunocompromised children. J Pediatr Infect Dis Soc. 2017;6(4):389–92.CrossRefGoogle Scholar
  74. 74.
    Krishna G, Sansone-Parsons A, Martinho M, Kantesaria B, Pedicone L. Posaconazole plasma concentrations in juvenile patients with invasive fungal infection. Antimicrob Agents Chemother. 2007;51(3):812–8.CrossRefGoogle Scholar
  75. 75.
    Vicenzi EB, Calore E, Decembrino N, Berger M, Perruccio K, Carraro F, et al. Posaconazole oral dose and plasma levels in pediatric hematology–oncology patients. Eur J Haematol. 2018;100(3):315–22.CrossRefGoogle Scholar
  76. 76.
    Chin A, Pergam SA, Fredricks DN, Hoofnagle AN, Baker KK, Jain R. Evaluation of posaconazole serum concentrations from delayed-release tablets in patients at high risk for fungal infections. Antimicrob Agents Chemother. 2017;61(10):e00569-17.CrossRefGoogle Scholar
  77. 77.
    Ray J, Campbell L, Rudham S, Nguyen Q, Marriott D. Posaconazole plasma concentrations in critically ill patients. Ther Drug Monit. 2011;33(4):387–92.CrossRefGoogle Scholar
  78. 78.
    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(5):1162–76.CrossRefGoogle Scholar
  79. 79.
    Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24:e1–38.CrossRefGoogle Scholar
  80. 80.
    Bellmann R. Pharmacodynamics and pharmacokinetics of antifungals for treatment of invasive aspergillosis. Curr Pharm Des. 2013;19(20):3629–47.CrossRefGoogle Scholar
  81. 81.
    Stockmann C, Constance JE, Roberts JK, Olson J, Doby EH, Ampofo K, et al. Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications. Clin Pharmacokinet. 2014;53(5):429–54.CrossRefGoogle Scholar
  82. 82.
    Dekkers BG, Bakker M, van der Elst KC, Sturkenboom MG, Veringa A, Span LF, et al. Therapeutic drug monitoring of posaconazole: an update. Curr Fungal Infect Rep. 2016;10(2):51–61.CrossRefGoogle Scholar
  83. 83.
    Nagappan V, Deresinski S. Reviews of anti-infective agents: posaconazole: a broad-spectrum triazole antifungal agent. Clin Infect Dis. 2007;45(12):1610–7.CrossRefGoogle Scholar
  84. 84.
    Panos G, Velissaris D, Karamouzos V, Matzaroglou C, Tylianakis M. Long QT syndrome leading to multiple cardiac arrests after posaconazole administration in an immune-compromised patient with sepsis: an unusual case report. Am J Case Rep. 2016;17:295–300.CrossRefGoogle Scholar
  85. 85.
    Sansone-Parsons A, Krishna G, Martinho M, Kantesaria B, Gelone S, Mant TG. Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus. Pharmacotherapy. 2007;27(6):825–34.CrossRefGoogle Scholar
  86. 86.
    Cho E, Chan H, Nguyen HM, Shayani S, Nakamura R, Pon D. Management of drug interaction between posaconazole and sirolimus in patients who undergo hematopoietic stem cell transplant. Pharmacotherapy. 2015;35(6):578–85.CrossRefGoogle Scholar
  87. 87.
    Peksa GD, Schultz K, Fung HC. Dosing algorithm for concomitant administration of sirolimus, tacrolimus, and an azole after allogeneic hematopoietic stem cell transplantation. J Oncol Pharm Pract. 2015;21(6):409–15.CrossRefGoogle Scholar
  88. 88.
    Moriyama B, Henning SA, Leung J, Falade-Nwulia O, Jarosinski P, Penzak SR, et al. Adverse interactions between antifungal azoles and vincristine: review and analysis of cases. Mycoses. 2012;55(4):290–7.CrossRefGoogle Scholar
  89. 89.
    Agarwal SK, DiNardo CD, Potluri J, Dunbar M, Kantarjian HM, Humerickhouse RA, et al. Management of venetoclax–posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments. Clin Ther. 2017;39(2):359–67.CrossRefGoogle Scholar
  90. 90.
    Dolton MJ, Ray JE, Chen SC, Ng K, Pont L, McLachlan AJ. Multicenter study of posaconazole therapeutic drug monitoring: exposure–response relationship and factors affecting concentration. Antimicrob Agents Chemother. 2012;56(11):5503–10.Google Scholar
  91. 91.
    Livermore J, Hope W. Evaluation of the pharmacokinetics and clinical utility of isavuconazole for treatment of invasive fungal infections. Expert Opin Drug Metabol Toxicol. 2012;8(6):759–65.CrossRefGoogle Scholar
  92. 92.
    Astellas Pharma US Inc. CresembaR (isavuconazonium sulfate): US prescribing information. 2015. Accessed 22 Mar 2018.
  93. 93.
    Schmitt-Hoffmann A, Desai A, Kowalski D, Pearlman H, Yamazaki T, Townsend R. Isavuconazole absorption following oral administration in healthy subjects is comparable to intravenous dosing, and is not affected by food, or drugs that alter stomach pH. Int J Clin Pharmacol Ther. 2016;54(8):572–80.CrossRefGoogle Scholar
  94. 94.
    Schmitt-Hoffmann A, Roos B, Heep M, Schleimer M, Weidekamm E, Brown T, et al. Single-ascending dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral, administrations (100, 200, and 400 milligrams) administrations of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother. 2006;50(1):279–85.CrossRefGoogle Scholar
  95. 95.
    European Medicines Agency. Cresemba: summary of product characteristics. 2015. Accessed 22 Mar 2018.
  96. 96.
    Schmitt-Hoffmann A, Roos B, Maares J, Heep M, Spickerman J, Weidekamm E, et al. Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy, volunteers. Antimicrob Agents Chemother. 2006;50(1):286–93.CrossRefGoogle Scholar
  97. 97.
    Pettit NN, Carver PL. Isavuconazole: a new option for the management of invasive fungal infections. Ann Pharmacother. 2015;49(7):825–42.CrossRefGoogle Scholar
  98. 98.
    Townsend RW, Akhtar S, Alcorn H, Berg JK, Kowalski DL, Mujais S, et al. Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics. Eur J Clin Pharmacol. 2017;73(3):669–78.CrossRefGoogle Scholar
  99. 99.
    Wilby KJ. A review of the clinical pharmacokinetics and pharmacodynamics of isavuconazole. Eur J Drug Metab Pharmacokinet. 2018;43(3):281–90.
  100. 100.
    Desai A, Kovanda L, Kowalski D, Lu Q, Townsend R, Bonate PL. Population pharmacokinetics of isavuconazole from phase 1 and phase 3 (SECURE) trials in adults and target attainment in patients with invasive infections due to Aspergillus and other filamentous fungi. Antimicrob Agents Chemother. 2016;60:5483–91.Google Scholar
  101. 101.
    Kovanda LL, Desai AV, Lu Q, Townsend RW, Akhtar S, Bonate P, Hope WW. Isavuconazole population pharmacokinetic analysis using nonparametric estimation in patients with invasive fungal disease (results from the VITAL study). Antimicrob Agents Chemother. 2016;60:4568–76.CrossRefGoogle Scholar
  102. 102.
    Donnelley MA, Zhu ES, Thompson GR III. Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections. Infect Drug Resist. 2016;9:79–86.Google Scholar
  103. 103.
    Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR III, VITAL and FungiScope Mucormycosis Investigators, et al. Isavuconazole treatment for mucormycosis: open-label trial and contemporaneous case–control analysis. Lancet Infect Dis. 2016;16(7):828–8371.CrossRefGoogle Scholar
  104. 104.
    Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760–9.Google Scholar
  105. 105.
    Murrell D, Bossaer JB, Carico R, Harirforoosh S, Cluck D. Isavuconazonium sulfate: a triazole prodrug for invasive fungal infections. Int J Pharm Pract. 2017;25(1):18–30.CrossRefGoogle Scholar
  106. 106.
    Groll AH, Desai A, Han D, Howieson C, Kato K, Akhtar S, et al. Pharmacokinetic assessment of drug–drug interactions of isavuconazole with the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Clin Pharmacol Drug Dev. 2017;6(1):76–85.CrossRefGoogle Scholar
  107. 107.
    Desai A, Yamazaki T, Dietz AJ, Kowalski D, Lademacher C, Pearlman H, et al. Pharmacokinetic and pharmacodynamic evaluation of the drug–drug interaction between isavuconazole and warfarin in healthy subjects. Clin Pharmacol Drug Dev. 2017;6(1):86–92.CrossRefGoogle Scholar
  108. 108.
    Lempers VJ, van den Heuvel JJ, Russel FG, Aarnoutse RE, Burger DM, Brüggemann RJ, et al. Inhibitory potential of antifungal drugs on ATP-binding cassette transporters P-glycoprotein, MRP1 to MRP5, BCRP, and BSEP. Antimicrob Agents Chemother. 2016;60(6):3372–9.CrossRefGoogle Scholar
  109. 109.
    De Sarro A, La Camera E, Fera MT. New and investigational triazole agents for the treatment of invasive fungal infections. J Chemother. 2008;20(6):661–71.CrossRefGoogle Scholar
  110. 110.
    Yamaguchi H. Potential of ravuconazole and its prodrugs as the new oral therapeutics for onychomycosis. Med Mycol J. 2016;57(4):E93–110.CrossRefGoogle Scholar
  111. 111.
    Pasqualotto AC, Thiele KO, Goldani LZ. Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole. Curr Opin Investig Drugs. 2010;11(2):165–74.Google Scholar
  112. 112.
    Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. J Antimicrob Chemother. 2008;61(Suppl 1):i19–30.CrossRefGoogle Scholar
  113. 113.
    Girmenia C, Finolezzi E. New-generation triazole antifungal drugs: review of the phase II and III trials. Clin Investig. 2011;1(11):1577–94.CrossRefGoogle Scholar
  114. 114.
    Olsen SJ, Mummaneni V, Rolan P, Norton J, Grasela DM. Ravuconazole single ascending oral dose study in healthy subjects. ICAAC Abstr. 2000;40:838.Google Scholar
  115. 115.
    Marino M, Mummaneni V, Norton J, Hadjilambris O, Pierce P. Ravuconazole exposure–response relationship in HIV + patients with oropharyngeal candidiasis (abstract J-1622). In: American Society for Microbiology, editor. Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago: American Society for Microbiology; 2001. p. 393.Google Scholar
  116. 116.
    Beale M, Queiroz-Telles F, Banhegyi D, Li N, Pierce PF. Randomized, double-blind study of the safety and antifungal activity of ravuconazole relative to fluconazole in esophageal candidiasis (abstract J-1621). In: American Society for Microbiology, editor. Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago: American Society for Microbiology; 2001. p. 392.Google Scholar
  117. 117.
    Yan JH, Marino MR, Smith RA, Kanamaluru V, O’Mara EM, Grasela DM. The effect of ravuconazole on the pharmacokinetics of nelfinavir in healthy male volunteers. J Clin Pharmacol. 2006;46(2):193–200.CrossRefGoogle Scholar
  118. 118.
    Hoenigl M, Prattes J, Neumeister P, Wölfler A, Krause R. Real-world challenges and unmet needs in the diagnosis and treatment of suspected invasive pulmonary aspergillosis in patients with haematological diseases: an illustrative case study. Mycoses. 2018;61(3):201–5.CrossRefGoogle Scholar
  119. 119.
    Perfect JR, Cornely OA, Heep M, Ostrosky-Zeichner L, Mullane KM, Maher R, et al. Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: challenges and lessons of the VITAL trial. Mycoses. 2018;61(7):420–9. (Epub ahead of print).
  120. 120.
    Hamada Y, Tokimatsu I, Mikamo H, Kimura M, Seki M, Takakura S, et al. Practice guidelines for therapeutic drug monitoring of voriconazole: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. J Infect Chemother. 2013;19(3):381–92.CrossRefGoogle Scholar
  121. 121.
    Chen L, Wang Y, Zhang T, Li Y, Meng T, Liu L, et al. Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential, analysis. BMC Infect Dis. 2018;18(1):155.CrossRefGoogle Scholar
  122. 122.
    Fatiguso G, Favata F, Zedda I, De Nicolò A, Cusato J, Avataneo V, et al. A simple high performance liquid chromatography–mass spectrometry method for therapeutic drug monitoring of isavuconazole and four other antifungal drugs in human plasma samples. J Pharm Biomed Anal. 2017;145:718–24.CrossRefGoogle Scholar
  123. 123.
    Wiederhold NP, Kovanda L, Najvar LK, Bocanegra R, Olivo M, Kirkpatrick WR, et al. Isavuconazole is effective for the treatment of experimental cryptococcal meningitis. Antimicrob Agents Chemother. 2016;60(9):5600–3.CrossRefGoogle Scholar
  124. 124.
    Jariwal R, Heidari A, Sandhu A, Patel J, Shoaepour K, Natarajan P, et al. Granulomatous invasive Aspergillus flavus infection involving the nasal sinuses and brain. J Investig Med High Impact Case Rep. 2018;6:2324709618770473. Scholar
  125. 125.
    Ellenbogen JR, Waqar M, Denning DW, Cooke RP, Skinner DW, Lesser T, Javadpour M. Posaconazole responsive cerebral aspergillosis in an immunocompetent adult. J Clin Neurosci. 2014;21(10):1825–7.CrossRefGoogle Scholar
  126. 126.
    Tsakiri S, Aneji C, Domonoske C, Mazur L, Benjamin DK Jr, Wootton SH. Voriconazole treatment for an infant with intractable Candida glabrata meningitis. Pediatr Infect Dis J. 2018;37(10):999–1001. (Epub ahead of print).
  127. 127.
    Kim T, Jancel T, Kumar P, Freeman AF. Drug–drug interaction between isavuconazole and tacrolimus: a case report indicating the need for tacrolimus drug-level monitoring. J Clin Pharm Ther. 2015;40(5):609–11. (Epub ahead of print).
  128. 128.
    Wang T, Yan M, Tang D, Xue L, Zhang T, Dong Y, et al. Therapeutic drug monitoring and safety of voriconazole therapy in patients with Child–Pugh class B and C cirrhosis: a multicenter study. Int J Infect Dis. 2018;72:49–54.CrossRefGoogle Scholar
  129. 129.
    Yamada T, Imai S, Koshizuka Y, Tazawa Y, Kagami K, Tomiyama N, et al. Necessity for a significant maintenance dosage reduction of voriconazole in patients with severe liver cirrhosis (Child–Pugh class C). Biol Pharm Bull. 2018;41(7):1112–8. (Epub ahead of print).
  130. 130.
    Merck Sharp & Dohme Limited. Noxafil 300 mg concentrate for solution for infusion. Summary of product characteristics. 2017. Accessed 14 Apr 2018.
  131. 131.
    Pfizer Limited. Cresemba 200 mg powder for concentrate for solution for infusion. Summary of product characteristics. 2017. Accessed 14 Apr 2018.
  132. 132.
    Fuhrman DY, Kane-Gill S, Goldstein SL, Priyanka P, Kellum JA. Acute kidney injury epidemiology, risk factors, and outcomes in critically ill patients 16–25 years of age treated in an adult intensive care unit. Ann Intensive Care. 2018;8(1):26.CrossRefGoogle Scholar
  133. 133.
    Radej J, Krouzecky A, Stehlik P, Sykora R, Chvojka J, Karvunidis T, et al. Pharmacokinetic evaluation of voriconazole treatment in critically ill patients undergoing continuous venovenous hemofiltration. Ther Drug Monit. 2011;33(4):393–7.CrossRefGoogle Scholar
  134. 134.
    Lutsar I, Roffey S, Troke P. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients. Clin Infect Dis. 2003;37(5):728–32.CrossRefGoogle Scholar
  135. 135.
    Duarte RF, López-Jiménez J, Cornely OA, Laverdiere M, Helfgott D, Haider S, et al. Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia. Antimicrob Agents Chemother. 2014;58(10):5758–65.CrossRefGoogle Scholar
  136. 136.
    Maertens J, Cornely OA, Ullmann AJ, Heinz WJ, Krishna G, Patino H, et al. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease. Antimicrob Agents Chemother. 2014;58(7):3610–7.CrossRefGoogle Scholar
  137. 137.
    Walsh TJ, Karlsson MO, Driscoll T, Arguedas AG, Adamson P, Saez-Llorens X, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother. 2004;48(6):2166–72.Google Scholar
  138. 138.
    Döring M, Stanchi KM, Queudeville M, Feucht J, Blaeschke F, Schlegel P, et al. Efficacy, safety and feasibility of antifungal prophylaxis with posaconazole tablet in paediatric patients after haematopoietic stem cell transplantation. J Cancer Res Clin Oncol. 2017;143(7):1281–92.CrossRefGoogle Scholar
  139. 139.
    Livermore J, Hope W. Evaluation of the pharmacokinetics and clinical utility of isavuconazole for treatment of invasive fungal infections. Expert Opin Drug Metab Toxicol. 2012;8(6):759–65.CrossRefGoogle Scholar
  140. 140.
    Ueda Y, Barbour N, Bronson JJ, Connolly TP, Dali M, Gao Q, et al. BMS-379224, a watersoluble prodrug of ravuconazole. Intersci Conf Antimicrob Agents Chemother. 2002;42:Abs F-817.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Zorica Jović
    • 1
  • Slobodan M. Janković
    • 2
    Email author
  • Dejana Ružić Zečević
    • 2
  • Dragan Milovanović
    • 2
  • Srđan Stefanović
    • 2
  • Marko Folić
    • 2
  • Jasmina Milovanović
    • 2
  • Marina Kostić
    • 2
  1. 1.Faculty of MedicineUniversity of NišNišSerbia
  2. 2.Faculty of Medical SciencesUniversity of KragujevacKragujevacSerbia

Personalised recommendations