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Clinical Pharmacokinetics and Pharmacodynamics of Isavuconazole

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Abstract

In March 2015, the extended-spectrum triazole antifungal isavuconazole was granted approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of invasive aspergillosis and mucormycosis. Isavuconaozle has activity against a broad range of yeasts, dimorphic fungi, and molds and is associated with fewer toxicities than voriconazole. It also has predictable pharmacokinetics in adults, fewer drug–drug interactions than many existing antifungal agents, and is available in both oral and β-cyclodextrin-free intravenous formulations. In this review, we explore what is known about the pharmacokinetics and pharmacodynamics of isavuconazole and look ahead to its expanding applications in clinical practice.

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References

  1. Warn PA, Sharp A, Denning DW. In vitro activity of a new triazole BAL4815, the active component of BAL8557 (the water-soluble prodrug), against Aspergillus spp. J Antimicrob Chemother. 2006;57(1):135–8.

    Article  CAS  Google Scholar 

  2. Cornely OA, Mullane KM, Ostrosky-Zeichner L, Maher RM, Croos-Dabrera R, Lu Q, et al. Isavuconazole for treatment of rare invasive fungal diseases. Mycoses. 2018. https://doi.org/10.1111/myc.12778.

    Article  PubMed  Google Scholar 

  3. Falces-Romero I, Quiles-Melero I, García-Rodríguez J. In vitro susceptibility of cryptic species of Aspergillus fumigatus to isavuconazole, itraconazole and voriconazole by means of E-test [in Spanish]. Rev Iberoam Micol. 2018. https://doi.org/10.1016/j.riam.2017.10.001.

    Article  PubMed  Google Scholar 

  4. Fung M, Schwartz BS, Doernberg SB, Langelier C, Lo M, Graff L, et al. Breakthrough invasive fungal infections on isavuconazole prophylaxis and treatment: what is happening in the real-world setting? Clin Infect Dis. 2018. https://doi.org/10.1093/cid/ciy260.

    Article  PubMed  Google Scholar 

  5. Lepak AJ, Marchillo K, Vanhecker J, Andes DR. Isavuconazole (BAL4815) pharmacodynamic target determination in an in vivo murine model of invasive pulmonary aspergillosis against wild-type and cyp51 mutant isolates of Aspergillus fumigatus. Antimicrob Agents Chemother. 2013;57(12):6284–9.

    Article  CAS  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. Guinea J, Peláez T, Recio S, Torres-Narbona M, Bouza E. In vitro antifungal activities of isavuconazole (BAL4815), voriconazole, and fluconazole against 1,007 isolates of zygomycete, Candida, Aspergillus, Fusarium, and Scedosporium species. Antimicrob Agents Chemother. 2008;52(4):1396–400.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. Pettit NN, Carver PL. Isavuconazole: a new option for the management of invasive fungal infections. Ann Pharmacother. 2015;49(7):825–42.

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16(7):828–37.

    Article  CAS  Google Scholar 

  14. Shirley M, Scott LJ. Isavuconazole: a review in invasive aspergillosis and mucormycosis. Drugs. 2016;76(17):1647–57.

    Article  CAS  Google Scholar 

  15. 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) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother. 2006;50(1):279–85.

    Article  CAS  Google Scholar 

  16. Ledoux MP, Denis J, Nivoix Y, Herbrecht R. Isavuconazole a new broad-spectrum azole Part 2 pharmacokinetics and clinical activity. J Mycol Med. 2018;28(1):15–22.

    Article  Google Scholar 

  17. Ahmed Y, Delaney S, Markarian A. Successful Isavuconazole therapy in a patient with acute invasive fungal rhinosinusitis and acquired immune deficiency syndrome. Am J Otolaryngol. 2016;37(2):152–5.

    Article  Google Scholar 

  18. Türel O. Newer antifungal agents. Expert Rev Anti Infect Ther. 2011;9(3):325–38.

    Article  Google Scholar 

  19. Roilides E, Antachopoulos C. Isavuconazole: an azole active against mucormycosis. Lancet Infect Dis. 2016;16(7):761–2.

    Article  CAS  Google Scholar 

  20. Kabulski GM, MacVane SH. Isavuconazole pharmacokinetics in a patient with cystic fibrosis following bilateral orthotopic lung transplantation. Transpl Infect Dis. 2018;55:e12878.

    Article  Google Scholar 

  21. Steinmann J, Dittmer S, Houbraken J, Buer J, Rath PM. In vitro activity of isavuconazole against Rasamsonia species. Antimicrob Agents Chemother. 2016;60(11):6890–1.

    Article  CAS  Google Scholar 

  22. Kovanda LL, Desai AV, Lu Q, Townsend RW, Akhtar S, Bonate P, et al. Isavuconazole population pharmacokinetic analysis using nonparametric estimation in patients with invasive fungal disease (results from the VITAL Study). Antimicrob Agents Chemother. 2016;60(8):4568–76.

    Article  CAS  Google Scholar 

  23. Badali H, Mohammadi R, Mashedi O, de Hoog GS, Meis JF. In vitro susceptibility patterns of clinically important Trichophyton and Epidermophyton species against nine antifungal drugs. Mycoses. 2015;58(5):303–7.

    Article  CAS  Google Scholar 

  24. Thompson GR, Wiederhold NP, Sutton DA, Fothergill A, Patterson TF. In vitro activity of isavuconazole against Trichosporon, Rhodotorula, Geotrichum, Saccharomyces and Pichia species. J Antimicrob Chemother. 2009;64(1):79–83.

    Article  CAS  Google Scholar 

  25. Wilson DT, Dimondi VP, Johnson SW, Jones TM, Drew RH. Role of isavuconazole in the treatment of invasive fungal infections. Ther Clin Risk Manag. 2016;12:1197–206.

    Article  CAS  Google Scholar 

  26. Townsend R, Kato K, Hale C, Kowalski D, Lademacher C, Yamazaki T, et al. Two phase 1, open-label, mass balance studies to determine the pharmacokinetics of 14 C-labeled isavuconazonium sulfate in healthy male volunteers. Clin Pharmacol Drug Dev. 2018;7(2):207–16.

    Article  CAS  Google Scholar 

  27. Petraitis V, Petraitiene R, Moradi PW, Strauss GE, Katragkou A, Kovanda LL, et al. Pharmacokinetics and concentration-dependent efficacy of isavuconazole for treatment of experimental invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2016;60(5):2718–26.

    Article  CAS  Google Scholar 

  28. Pfaller MA, Messer SA, Rhomberg PR, Jones RN, Castanheira M. In vitro activities of isavuconazole and comparator antifungal agents tested against a global collection of opportunistic yeasts and molds. J Clin Microbiol. 2013;51(8):2608–16.

    Article  CAS  Google Scholar 

  29. Espinel-Ingroff A, Chowdhary A, Gonzalez GM, Guinea J, Hagen F, Meis JF, et al. Multicenter study of isavuconazole MIC distributions and epidemiological cutoff values for the Cryptococcus neoformans-Cryptococcus gattii species complex using the CLSI M27-A3 broth microdilution method. Antimicrob Agents Chemother. 2015;59(1):666–8.

    Article  CAS  Google Scholar 

  30. Seifert H, Aurbach U, Stefanik D, Cornely O. In vitro activities of isavuconazole and other antifungal agents against Candida bloodstream isolates. Antimicrob Agents Chemother. 2007;51(5):1818–21.

    Article  CAS  Google Scholar 

  31. 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.

    Article  CAS  Google Scholar 

  32. Desai A, Schmitt-Hoffmann AH, Mujais S, Townsend R. Population Pharmacokinetics of isavuconazole in subjects with mild or moderate hepatic impairment. Antimicrob Agents Chemother. 2016;60(5):3025–31.

    Article  CAS  Google Scholar 

  33. Schmitt-Hoffmann A, Roos B, Spickermann J, Heep M, Peterfaí E, Edwards DJ, et al. Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557. Antimicrob Agents Chemother. 2009;53(11):4885–90.

    Article  CAS  Google Scholar 

  34. Miceli MH, Kauffman CA. Isavuconazole: a new broad-spectrum triazole antifungal agent. Clin Infect Dis. 2015;61(10):1558–65.

    Article  CAS  Google Scholar 

  35. Donnelley MA, Zhu ES, Thompson GR. Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections. Infect Drug Resist. 2016;9:79–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 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(9):5483–91.

    Article  CAS  Google Scholar 

  37. Kovanda LL, Petraitiene R, Petraitis V, Walsh TJ, Desai A, Bonate P, et al. Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints. J Antimicrob Chemother. 2016;71(7):1885–91.

    Article  CAS  Google Scholar 

  38. Collins PW. Personalized prophylaxis. Haemophilia. 2012;18(Suppl. 4):131–5.

    Article  Google Scholar 

  39. McCarthy MW, Denning DW, Walsh TJ. Future research priorities in fungal resistance. J Infect Dis. 2017;216(Suppl. 3):S484–92.

    Article  CAS  Google Scholar 

  40. Cornely OA, Böhme A, Schmitt-Hoffmann A, Ullmann AJ. Safety and pharmacokinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia patients with neutropenia: results of a phase 2, dose escalation study. Antimicrob Agents Chemother. 2015;59(4):2078–85.

    Article  CAS  Google Scholar 

  41. Warn PA, Sharp A, Parmar A, Majithiya J, Denning DW, Hope WW. Pharmacokinetics and pharmacodynamics of a novel triazole, isavuconazole: mathematical modeling, importance of tissue concentrations, and impact of immune status on antifungal effect. Antimicrob Agents Chemother. 2009;53(8):3453–61.

    Article  CAS  Google Scholar 

  42. Lepak AJ, Marchillo K, VanHecker J, Diekema D, Andes DR. Isavuconazole pharmacodynamic target determination for Candida species in an in vivo murine disseminated candidiasis model. Antimicrob Agents Chemother. 2013;57(11):5642–8.

    Article  CAS  Google Scholar 

  43. Wilby KJ. A Review of the clinical pharmacokinetics and pharmacodynamics of isavuconazole. Eur J Drug Metab Pharmacokinet. 2017. https://doi.org/10.1007/s13318-017-0445-7.

    Article  PubMed  Google Scholar 

  44. Seyedmousavi S, Brüggemann RJ, Meis JF, Melchers WJ, Verweij PE, Mouton JW. Pharmacodynamics of isavuconazole in an Aspergillus fumigatus mouse infection model. Antimicrob Agents Chemother. 2015;59(5):2855–66.

    Article  CAS  Google Scholar 

  45. Box H, Livermore J, Johnson A, McEntee L, Felton TW, Whalley S, et al. Pharmacodynamics of isavuconazole in a dynamic in vitro model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2015;60(1):278–87.

    Article  Google Scholar 

  46. 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.

    Article  CAS  Google Scholar 

  47. Yamazaki T, Desai A, Goldwater R, Han D, Lasseter KC, Howieson C, et al. Pharmacokinetic interactions between isavuconazole and the drug transporter substrates atorvastatin, digoxin, metformin, and methotrexate in healthy subjects. Clin Pharmacol Drug Dev. 2017;6(1):66–75.

    Article  CAS  Google Scholar 

  48. 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.

    Article  CAS  Google Scholar 

  49. Ledoux MP, Toussaint E, Denis J, Herbrecht R. New pharmacological opportunities for the treatment of invasive mould diseases. J Antimicrob Chemother. 2017;72(1):i48–58.

    Article  CAS  Google Scholar 

  50. Townsend R, Dietz A, Hale C, Akhtar S, Kowalski D, Lademacher C, et al. Pharmacokinetic evaluation of CYP3A4-mediated drug-drug interactions of isavuconazole with rifampin, ketoconazole, midazolam, and ethinyl estradiol/norethindrone in healthy adults. Clin Pharmacol Drug Dev. 2017;6(1):44–53.

    Article  CAS  Google Scholar 

  51. Yamazaki T, Desai A, Goldwater R, Han D, Howieson C, Akhtar S, et al. Pharmacokinetic effects of isavuconazole coadministration with the cytochrome P450 enzyme substrates bupropion, repaglinide, caffeine, dextromethorphan, and methadone in healthy subjects. Clin Pharmacol Drug Dev. 2017;6(1):54–65.

    Article  CAS  Google Scholar 

  52. Yamazaki T, Desai A, Han D, Kato K, Kowalski D, Akhtar S, et al. Pharmacokinetic interaction between isavuconazole and a fixed-dose combination of lopinavir 400 mg/ritonavir 100 mg in healthy subjects. Clin Pharmacol Drug Dev. 2017;6(1):93–101.

    Article  CAS  Google Scholar 

  53. Gebremariam T, Wiederhold NP, Alqarihi A, Uppuluri P, Azie N, Edwards JE, et al. Monotherapy or combination therapy of isavuconazole and micafungin for treating murine mucormycosis. J Antimicrob Chemother. 2017;72(2):462–6.

    Article  CAS  Google Scholar 

  54. Ordaya EE, Alangaden GJ. Real-life use of isavuconazole in patients intolerant to other azoles. Clin Infect Dis. 2016;63(11):1529–30.

    Article  CAS  Google Scholar 

  55. Perkhofer S, Lechner V. Lass-Flörl C; European Committee on Antimicrobial Susceptibility Testing. In vitro activity of Isavuconazole against Aspergillus species and zygomycetes according to the methodology of the European Committee on Antimicrobial Susceptibility Testing. Antimicrob Agents Chemother. 2009;53(4):1645–7.

    Article  CAS  Google Scholar 

  56. González GM. In vitro activities of isavuconazole against opportunistic filamentous and dimorphic fungi. Med Mycol. 2009;47(1):71–6.

    Article  Google Scholar 

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Authors and Affiliations

  1. Weill Cornell Medical College, 525 East 68 Street, Box 331, New York, NY, 10065, USA

    Matthew W. McCarthy, Ruta Petraitiene, Thomas J. Walsh & Vidmantas Petraitis

  2. NIH Clinical Center, Pharmacy Department, National Heart Lung and Blood Instititute, Bethesda, MD, USA

    Brad Moriyama

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Correspondence to Matthew W. McCarthy.

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No sources of funding were received for the preparation of this article.

Conflict of interest

Matthew W. McCarthy has served as a paid consultant to Allergan. Thomas J. Walsh receives research grants for experimental and clinical antimicrobial pharmacotherapeutics from Astellas, Cubist, Theravance, the Medicines Company, Allergan, Novartis, Merck, and Pfizer. He has served as a consultant to Astellas, Actavis, ContraFect, Drais, iCo, Novartis, Pfizer, Methylgene, SigmaTau, and Trius. Brad Moriyama, Ruta Petraitiene, and Vidmantas Petraitis have no conflicts of interest directly relevant to the content of this article.

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McCarthy, M.W., Moriyama, B., Petraitiene, R. et al. Clinical Pharmacokinetics and Pharmacodynamics of Isavuconazole. Clin Pharmacokinet 57, 1483–1491 (2018). https://doi.org/10.1007/s40262-018-0673-2

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