472
Views
5
CrossRef citations to date
0
Altmetric
Drug Evaluation

Evaluating posaconazole, its pharmacology, efficacy and safety for the prophylaxis and treatment of fungal infections

&
Pages 175-199 | Received 02 Apr 2021, Accepted 18 Oct 2021, Published online: 10 Nov 2021

References

  • Bongomin F, Gago S, Oladele RO, et al. Global and multi-national prevalence of fungal diseases—estimate precision. J Fungi Basel. 2017;3(4):57.
  • Chang YL, Yu SJ, Heitman J, et al. New facets of antifungal therapy. Virulence. 2017;8(2):222–236.
  • Schiller DS, Fung HB. Posaconazole: an extended-spectrum triazole antifungal agent. Clin Ther. 2007;29(9):1826–1886.
  • Wall G, Lopez-Ribot JL. Current antimycotics, new prospects, and future approaches to antifungal therapy. Antibiot Basel. 2020;9(8):445.
  • Odds F, Brown D, Gow N. Antifungal agents: mechanisms of action. Trends Microbiol. 2003;11(6):272–279.
  • Wade RL, Chaudhari P, Natoli JL, et al. Nephrotoxicity and other adverse events among inpatients receiving liposomal amphotericin B or amphotericin B lipid complex. Diagn Microbiol Infect Dis. 2013;76(3):361–367.
  • Denning DW. Echinocandin antifungal drugs. Lancet. 2003;362(9390):1142–1151.
  • Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America. Clin Infect Dis. 2016;62:e1–e50.
  • Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the infectious diseases society of America. Clin Infect Dis. 2008;46:327–360.
  • Sabatelli F, Patel R, Mann PA, et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother. 2006;50(6):2009–2015.
  • Moore JN, Healy JR, Kraft WK. Pharmacologic and clinical evaluation of posaconazole. Expert Rev Clin Pharmacol. 2015;8(3):321–334.
  • Li Y, Theuretzbacher U, Clancy CJ, et al. Pharmacokinetic/pharmacodynamic profile of posaconazole. Clin Pharmacokinet. 2010;49(6):379–396.
  • Noxafil. EPAR-scientific discussion. [Internet]. London (UK): European Medicines Agency 2005. 1–37. [cited 2021 Feb 20]. Available from: https://www.ema.europa.eu/en/documents/scientific-discussion/noxafil-epar-scientific-discussion_en.pdf
  • Xiao L, Madison V, Chau AS, et al. Three-dimensional models of wild-type and mutated forms of cytochrome P450 14α-sterol demethylases from aspergillus fumigatus and Candida albicans provide insights into posaconazole binding. Antimicrob Agents Chemother. 2004;48(2):568–574.
  • Ghannoum M, Rice L. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol. 1999;12(4):501–517.
  • Whaley SG, Berkow EL, Rybak JM, et al. Azole antifungal resistance in Candida albicans and emerging non-albicans Candida species. Front Microbiol. 2016;7:2173.
  • Torres H, Hachem R, Chemaly R, et al. Posaconazole: a broad-spectrum triazole anti-fungal. Lancet Infect Dis. 2007;5(12):775–785.
  • Da Silva-hellwig AH, Heidrich D, Zanette RA, et al. In vitro susceptibility of chromoblastomycosis agents to antifungal drugs: a systematic review. J Glob Antimicrob Resist. 2019;16:108–114.
  • European Medicines Agency. ANNEX I. Summary of product characteristics [Internet]. EMA; 2020. [cited 2021 Feb 02]. Available from: https://www.ema.europa.eu/en/documents/product-information/noxafil-epar-product-information_en.pdf.
  • Sun QN, Fothergill AW, McCarthy DI, et al. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob Agents Chemother. 2002;46(5):1581–1582.
  • Shaukat A, Ansari NA, Wali WA, et al. Experience of treating Candida auris cases at a general hospital in the state of Qatar. IDCases. 2021;23:e01007.
  • Pfaller MA, Messer SA, Boyken L, et al. Global trends in the antifungal susceptibility of cryptococcus neoformans (1990 to 2004). J Clin Microbiol. 2005;43(5):2163–2167.
  • Diekema DJ, Messer SA, Hollis RJ, et al. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol. 2003;41(8):3623–3626.
  • Rationale document for EUCAST clinical breakpoints agent posaconazole citation of EUCAST documents [Internet]. 2020. [cited 2021 Feb 17]. Available from: http://www.EUCAST.org.http://www.eucast.org.
  • Schering-Plough news release. Schering-Schering Plough announces FDA approval of NOXAFIL ® (posaconazole) for prevention of invasive fungal infections. Kenilworth (NJ): Schering-Plough; [Internet]. 2006 [cited 2006 Jan 10]. Available from: http://www.scheringplough.com/schering_plough/news/release.jsp?releaselD=906202.
  • Guarascio AJ, Slain D. Review of the new delayed-release oral tablet and intravenous dosage forms of posaconazole. Pharmacotherapy. 2015;35(2):208–219.
  • Merck & Co. Noxafil (Posaconazole). Product monograph. Whitehouse Station, NJ: Merck & Co. 2020. [cited 2021 Feb 12]. Available from: https://www.merck.com/product/usa/pi_circulars/n/noxafil/noxafil_pi.pdf
  • McKeage K. Posaconazole: a review of the gastro-resistant tablet and intravenous solution in invasive fungal infections. Drugs. 2015;75(4):397–406.
  • Winchell GA, Greef RD, Wrishko RE, et al. 1558. A population pharmacokinetic model for posaconazole intravenous solution and oral powder for suspension formulations in pediatric patients with neutropenia. Open Forum Infect Dis. 2019;6(Supplement_2):S569–S569.
  • Groll AH, Abdel-Azim H, Lehrnbecher T, et al. Pharmacokinetics and safety of posaconazole intravenous solution and powder for oral suspension in children with neutropenia: an open-label, sequential dose-escalation trial. Int J Antimicrob Agents. 2020;56(3):12–13.
  • A phase 2, open-label, non-comparative clinical trial to study the safety and efficacy of posaconazole (POS, MK-5592) in pediatric participants aged 2 to less than 18 years with invasive aspergillosis. EudraCT 2019-002267-10, [Internet]. [cited 2021 Feb 14]. EudraCT 2019-002267-10, [Internet]: www.clinicaltrials.gov.
  • A phase 2, open-label, single-arm, sequential-panel study to evaluate the pharmacokinet-ics, safety, and tolerability of posaconazole (POS, MK-5592) intravenous and powder for oral suspension formulations in pediatric participants from birth to <2 years of age with possible, probable, or proven invasive fungal infection. EudraCT 2019-003842-34. [Internet]. [cited 2021 Feb 13]. EudraCT 2019-003842-34. [Internet]: www.clinicaltrials.gov.
  • Ezzet F, Wexler D, Courtney R, et al. Oral bioavailability of posaconazole in fasted healthy subjects comparison between three regimens and basis for clinical dosage recommendations. Clin Pharmacokinet. 2005;44(2):211–220.
  • Krishna G, Ma L, Martinho M, et al. 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):2725–2730.
  • Ullmann AJ, Cornely OA, Burchardt A, 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):658–666.
  • Chen L, Krekels EHJ, Verweij PE, et al. Pharmacokinetics and pharmacodynamics of posaconazole. Drugs. 2020;80(7):671–695.
  • Crombag M, Huisman C, Kemper E, et al. Posaconazole treatment in hematology patients: a pilot study of therapeutic drug monitoring. Ther Drug Monit. 2012;34(3):320–325.
  • Courtney R, Pai S, Laughlin M, et al. Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother. 2003;47(9):2788–2795.
  • Krishna G, Ma L, Martinho M, et al. 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):4196–4201.
  • Krishna G, Ma L, Vickery D, et al. Effect of varying amounts of a liquid nutritional supplement on the pharmacokinetics of posaconazole in healthy volunteers. Antimicrob Agents Chemother. 2009;53(11):4749–4752.
  • Krishna G, Moton A, Ma L, et al. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother. 2009;53(3):958–966.
  • Courtney R, Wexler D, Radwanski E, et al. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol. 2004;57(2):218–222.
  • Walravens J, Brouwers J, Spriet I, et al. Effect of pH and comedication on gastrointestinal absorption of posaconazole. Clin Pharmacokinet. 2011;50(11):725–734.
  • Committee for Medicinal Products for Human Use (CHMP). Posaconazole tablet assessment report. [Internet]. European Medicines Agency; 2014. [cited 2021 Sep 02]. Available from: https://www.ema.europa.eu/en/documents/variation-report/noxafil-h-c-610-x-0028-epar-scientific-discussion-extension_en.pdf
  • Dolton MJ, Ray JE, Chen SCA, et al. Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother. 2012;56(11):5503–5510.
  • Kraft WK, Chang PS, Iersel MLPSV, et al. Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects. Antimicrob Agents Chemother. 2014;58(7):4020–4025.
  • Duarte RF, López-Jiménez J, Comely OA, 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):5758–5765.
  • Cornely OA, Duarte RF, Haider S, et al. Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother. 2016;71(3):718–726.
  • Leclerc E, Combarel D, Uzunov M, et al. 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.
  • Chae H, Cho SY, Yi Y, et al. Evaluation of posaconazole plasma concentrations achieved with the delayed-release tablets in Korean high-risk patients with haematologic malignancy. Mycoses. 2020;63(2):131–138.
  • Jung DS, Tverdek FP, Kontoyiannis DP. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity. Antimicrob Agents Chemother. 2014;58(11):6993–6995.
  • Maertens J, Cornely OA, Ullmann AJ, 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):3610–3617.
  • Li H, Wei Y, Zhang S, et al. Pharmacokinetics and safety of posaconazole administered by intravenous solution and oral tablet in healthy chinese subjects and effect of food on tablet bioavailability. Clin Drug Investig. 2019;39(11):1109–1116.
  • Posaconazole Injection, Noxafil. [Internet]. FDA/Center for drug evaluation and research.; 2014 Accessed: 02/ 03/ 2021. [Internet]. [Internet]: www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205596Orig1s000MedR.pdf.
  • Kersemaekers WM, Iersel TV, Nassander U, et al. Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects. Antimicrob Agents Chemother. 2015;59(2):1246–1251.
  • Cornely OA, Robertson MN, Haider S, 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):3406–3413.
  • Krieter P, Flannery B, Musick T, et al. Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agent Chemother. 2004;48(9):3543–3551.
  • Kim H, Kumari P, Laughlin M, et al. Use of high-performance liquid chromatographic and microbiological analyses for evaluating the presence or absence of active metabolites of the antifungal posaconazole in human plasma. J Chromatogr A. 2003;987(1–2):243–248.
  • Ghosal A, Hapangama N, Yuan Y, et al. Identification of human UDP-Glucoronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (NOXAFIL). Drug Metab Dispos. 2004;32(2):267–271.
  • Suh HJ, Yoon SH, Yu K-S, et al. The genetic polymorphism UGT1A4*3 is associated with low posaconazole plasma concentrations in hematological malignancy patients receiving the oral suspension. Antimicrob Agents Chemother. 2018;62(7):e02230–17.
  • Nagappan V, Deresinski S. Posaconazole: a broad-spectrum triazole antifungal agent. Clin Infect Dis. 2007;45(12):1610–1617.
  • Liu K, Wu D, Li J, et al. Pharmacokinetics and safety of posaconazole tablet formulation in chinese participants at high risk for invasive fungal infection. Adv Ther. 2020;37(5):2493–2506.
  • Wong TY, Loo YS, Veettil SK, et al. Efficacy and safety of posaconazole for the prevention of invasive fungal infections in immunocompromised patients: a systematic review with meta-analysis and trial sequential analysis. Sci Rep. 2020;10(1):14575.
  • Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356(4):348–359.
  • Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356(4):335–347.
  • Cornely OA, Ullmann AJ. Numbers needed to treat with posaconazole prophylaxis to prevent invasive fungal infection and death. Clin Infect Dis. 2008;46(10):1626–1627.
  • Shen Y, Huang X, Wang J, et al. Posaconazole vs. fluconazole as invasive fungal infection prophylaxis in China: a multicenter, randomized, open-label study. Int J Clin Pharmacol Ther. 2013;51(9):738–745.
  • Chen X, Wang J, Wang S, et al. Real-world assessment of the effectiveness of posaconazole for the prophylaxis and treatment of invasive fungal infections in hematological patients: a retrospective observational study. Medicine (Baltimore). 2021;100(30):e26772.
  • Patterson TF, Thompson GR, Denning DW, et al. Executive summary: practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America. Clin Inf Dis. 2016;63(4):433–442.
  • Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24:e1–e38.
  • Warris A, Lehrnbecher T, Roilides E, et al. ESCMID-ECMM guideline: diagnosis and management of invasive aspergillosis in neonates and children. Clin Microbiol Infect. 2019;25:1096–1113.
  • Stelzer D, Weber A, Ihle F, et al. Posaconazole liquid vs tablet formulation in lung transplant recipients. Mycoses. 2018;61(3):186–194.
  • Kallee S, Scharf C, Schroeder I, et al. Comparing posaconazole and itraconazole for antifungal prophylaxis in critically ill lung transplant recipients: efficacy and plasma concentrations. Transpl Infect Dis [Internet]. 2021 cited 2021 Aug 25;23(4). DOI:https://doi.org/10.1111/tid.13675;
  • Wang J, Zhou M, Xu JY, et al. Comparison of antifungal prophylaxis drugs in patients with hematological disease or undergoing hematopoietic stem cell transplantation: a systematic review and network meta-analysis. JAMA Network Open. 2020;3(10):e2017652–undefined.
  • Cumpston A, Caddell R, Shillingburg A, et al. Superior serum concentrations with posaconazole delayed-release tablets compared to suspension formulation in hematological malignancies. Antimicrob Agents Chemother. 2017;59(8):4424–4428.
  • Oh J, Kang CI, Kim SH, et al. Antifungal prophylaxis with posaconazole tablet and oral suspension in patients with haematologic malignancy: therapeutic drug monitoring, efficacy and risk factors for the suboptimal level. Mycoses. 2020;63(1):89–94.
  • Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European confederation of medical mycology in cooperation with the mycoses study group education and research consortium. Lancet Infect Dis. 2019;19(12):E405–21.
  • Van Burik JAH, Hare RS, Solomon H, et al. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis. 2006;42(7):e61–5.
  • Alexander B, Perfect JR, Daly J, et al. Posaconazole as salvage therapy in patients with invasive fungal infections after solid organ transplant. Transplantation. 2008;86(6):791–796.
  • Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44(1):2–12.
  • Heimann SM, Penack O, Heinz WJ, et al. Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: a retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals. Int J Infect Dis. 2019;83:130–138.
  • Van Der Elst KCM, Brouwers CHS, Van Der Heuvel ER, et al. Subtherapeutic posaconazole exposure and treatment outcome in patients with invasive fungal disease. Ther Drug Monit. 2015;37(6):766–771.
  • Epstein DJ, Seo SK, Huang YT, et al. Micafungin versus posaconazole prophylaxis in acute leukemia or myelodysplastic syndrome: a randomized study. J Infect. 2018;77(3):227–234.
  • Furuno JP, Tallman GB, Noble BN, et al. Clinical outcomes of oral suspension versus delayed-release tablet formulations of posaconazole for prophylaxis of invasive fungal infections. Antimicrob Agents Chemother. 2018;62(10):1–10.
  • Gangneux J-P, Padoin C, Michallet M, et al. Outcomes of antifungal prophylaxis in high-risk haematological patients (AML under intensive chemotherapy): the SAPHIR prospective multicentre study. J Fungi. 2020;6(4):281.
  • Molina I, Prat JG, Salvador F, et al. Randomized trial of posaconazole and benznidazole for chronic chagas’ disease. N Engl J Med. 2014;370(20):1899–1908.
  • Manesh A, John AO, Mathew B, et al. Posaconazole: an emerging therapeutic option for invasive rhino-orbito-cerebral mucormycosis. Mycoses. 2016;59(12):765–772.
  • Zhang S, He Y, Jiang E, et al. Efficacy and safety of posaconazole in hematopoietic stem cell transplantation patients with invasive fungal disease. Future Microbiol. 2017;12(15):1371–1379.
  • Ojeda-Diezbarroso K, Aguilar-Rascón J, Jiménez-Juárez RN, et al. Successful posaconazole salvage therapy for rhinocerebral mucormycosis in a child with leukemia. Review of the literature. Rev Iberoam Micol. 2019;36(3):160–164.
  • Zhang S, Zhang P, Wang Z, et al. Posaconazole oral suspension as salvage therapy for invasive fungal disease in patients with hematological diseases. Future Microbiol. 2019;14(6):477–488.
  • Maertens JA, Rahav G, Lee D-G, et al. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial. Lancet. 2021;397(10273): 499–509.
  • Vazquez J, Skiest D, Nieto L, et al. A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/AIDS. Clin Infect Dis. 2006;42(8):1179–1186.
  • Skiest DJ, Vazquez JA, Anstead GM, et al. Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis. 2007;44(4):607–614.
  • European Medicines Agency. Noxafil. EPAR. Product information. ANNEX I summary of product characteristics [Internet]. 2020. [cited 2021 Feb 02]. Available from: https://www.ema.europa.eu/en/documents/product-information/noxafil-epar-product-information_en.pdf
  • Beredaki M-I, Arendrup MC, and Andes D, et al. The role of new posaconazole formulations in the treatment of Candida albicans infections: data from an in vitro pharmacokinetic-pharmacodynamic model. Antimicrob Agent Chemother. 2021;65(4):e01292–20.
  • Vehreschild JJ, Birtel A, Vehreschild MJGT, et al. Mucormycosis treated with posaconazole: review of 96 case reports. Crit Rev Microbiol. 2013;39(3):310–324.
  • Groll AH, Schrey D. The current role of posaconazole in managing zygomycosis. Curr Fungal Infect Rep. 2011;5(1):29–33.
  • Schauwvlieghe AFAD, Buil JB, Verweij PE, et al. High‐dose posaconazole for azole‐resistant aspergillosis and other difficult‐to‐treat mould infections. Mycoses. 2020;63(2):122–130.
  • Nett JE, Andes DR. Antifungal agents. Infect Clin North Am. 2016;30(1):51–83.
  • Reinwald M, Uharek L, Lampe D, et al. Limited penetration of posaconazole into cerebrospinal fluid in an allogeneic stem cell recipient with invasive pulmonary aspergillosis. Bone Marrow Transpl. 2009;44(4):269–270.
  • Ashley ED. Antifungal drugs: special problems treating central nervous system infections. J Fungi Basel. 2019;5(4):97.
  • Pitisuttithum P, Negroni R, Graybill JR, et al. Activity of posaconazole in the treatment of central nervous system fungal infections. J Antimicrob Chemother. 2005;56(4):745–755.
  • Clark NM, Grim SA, Lynch JP. Posaconazole: use in the prophylaxis and treatment of fungal infections. Semin Respir Crit Care Med. 2015;36(5):767–785.
  • Raad II, Hachem RY, Herbrecht R, et al. Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions. Clin Infect Dis. 2006;42(10):1398–1403.
  • Herbrecht R, Kessler R, Kravanja C, et al. Successful treatment of Fusarium proliferatum pneumonia with posaconazole in a lung transplant recipient. J Heart Lung Transpl. 2004;23(12):1451–1454.
  • Al Yazidi LS, Huynh J, Britton PN, et al. Endobronchial fusariosis in a child following bilateral lung transplant. Med Mycol Case Rep. 2019;23:77–80.
  • Sprute R, Salmanton-García J, and Sal E, et al. Characterization and outcome of invasive infections due to Paecilomyces variotii: analysis of patients from the FungiScope® registry and literature reports. J Antimicrob Chemother. 2020;76(3): 765–774.
  • Mondolfi AEP, Stavropoulos C, Gelanew T, et al. Successful treatment of old world cutaneous leishmaniasis caused by leishmania infantum with posaconazole. Antimicrob Agents Chemother. 2011;55(4):1774–1776.
  • Ashbee HR, Barnes RA, Johnson EM, et al. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British society for medical mycology. J Antimicrob Chemother. 2014;69(5):1162–1176.
  • Maertens JA, Girmenia C, Brüggemann RJ, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on infections in leukaemia. J Antimicrob Chemother. 2018;73:3221–3231.
  • Dolton MJ, Ray JE, Marriott D, et al. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother. 2012;56(6):2806–2813.
  • Jang SH, Colangelo PM, Gobburu JVS. Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin Pharmacol Ther. 2010;88(1):115–119.
  • Chen L, Wang Y, Zhang T, 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.
  • European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Posaconazole injection assessment report: EPAR-assessment report-Variation. [Internet]. 2014 [cited 2021 Jan 15]. Available from: https://www.ema.europa.eu/en/documents/variation-report/noxafil-h-c-610-x-0033-epar-assessment-report-variation_en.pdf.
  • Seyedmousavi S, Mouton JW, Melchers WJG, et al. The role of azoles in the management of azole-resistant aspergillosis: from the bench to the bedside. Drug Resist Updat. 2014;17(3):37–50.
  • Gautier-Veyret E, Bolcato L, Roustit M, et al. Treatment by posaconazole tablets, compared to posaconazole suspension, does not reduce variability of posaconazole trough concentrations. Antimicrob Agents Chemother. 2019;63(10):1–8.
  • Kraljevic M, Khanna N, and Medinger M, et al. Clinical considerations on posaconazole administration and therapeutic drug monitoring in allogeneic hematopoietic cell transplant recipients. Med Mycol. 2021;59(7):701–711.
  • Dekkers BGJ, Bakker M, Elst KCMVD, et al. Therapeutic drug monitoring of posaconazole: an update. Curr Fungal Infect Rep. 2016;10(2):51–61.
  • Elkayal O, Spriet I, Uyttebroeck A, et al. A population pharmacokinetic modeling and simulation study of posaconazole oral suspension in immunocompromised pediatric patients: a short communication. Ther Drug Monit. 2021;43(4):512–518.
  • Yang M, Cheng L, Dai Q, et al. A novel cryptococcal meningitis therapy: the combination of amphotericin B and posaconazole promotes the distribution of amphotericin B in the brain tissue. Biomed Res Int. 2020;2020:8878158.
  • Krishna G, Vickery D, Ma L, et al. Lack of pharmacokinetic drug interaction between oral posaconazole and caspofungin or micafungin. J Clin Pharmacol. 2011;51(1):84–92.
  • Lellek H, Waldenmaier D, Dahlke J, et al. Caspofungin plus posaconazole as salvage therapy of invasive fungal infections in immunocompromised patients. Mycoses. 2011;54:39–44.
  • Miller MA, Molina KC, Gutman JA, et al. Mucormycosis in hematopoietic cell transplant recipients and in patients with hematological malignancies in the era of new antifungal agents. Open Forum Infect Dis. 2021;8(2). DOI:https://doi.org/10.1093/ofid/ofaa646.
  • Riat A, Plojoux J, Gindro K, et al. Azole resistance of environmental and clinical aspergillus fumigatus isolates from Switzerland. Antimicrob Agents Chemother [Internet]. 2018 [cited 2021 Aug 22];62. Available from: https://journals.asm.org/doi/https://doi.org/10.1128/AAC.02088-17.
  • Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect Dis. 2017;17(12):e383–e392.
  • Sanglard D. Emerging threats in antifungal-resistant fungal pathogens. Front Med Lausanne. 2016;3:1–10.
  • Li X, Brown N, Chau AS, et al. Changes in susceptibility to posaconazole in clinical isolates of Candida albicans. J Antimicrob Chemother. 2003;53(1):74–80.
  • Munayyer HK, Mann PA, Chau AS, et al. Posaconazole is a potent inhibitor of sterol 14α-demethylation in yeasts and molds. Antimicrob Agents Chemother. 2004;48(10):3690–3696.
  • Groll AH, Walsh TJ. Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev Anti Infect Ther. 2005;3(4):467–487.
  • Lehrnbecher T, Attarbaschi A, Duerken M, et al. Posaconazole salvage treatment in paediatric patients: a multicentre survey. Eur J Clin Microbiol Infect Dis. 2010;29(8):1043–1045.
  • Vicenzi EB, Cesaro S. Posaconazole in immunocompromised pediatric patients. Expert Rev Anti Infect Ther. 2018;16(7):543–552.
  • Tragiannidis A, Herbrüggen H, Ahlmann M, et al. Plasma exposures following posaconazole delayed-release tablets in immunocompromised children and adolescents. J Antimicrob Chemother. 2019;74(12):3573–3578.
  • Welzen M, Brüggemann RJ, and Van Den Berg JM, et al. A twice daily posaconazole dosing algorithm for children with chronic granulomatous disease. Pediatr Infect J. 2011;30(9):794–797.
  • Bernardo V, Miles A, Fernandez AJ, et al. Initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children, adolescents, and young adults receiving delayed-release tablet and intravenous posaconazole. Pediatr Transpl. 2020;24(6):e13777.
  • Ramos JT, Romero CA, Belda S, et al. Clinical practice update of antifungal prophylaxis in immunocompromised children. Rev Esp Quimioter. 2019;32:410–425.
  • Döring M, Blume O, Haufe S, et al. Comparison of itraconazole, voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation. Eur J Clin Microbiol Infect Dis. 2014;33(4):629–638.
  • Döring M, Stanchi KMC, Queudeville M, 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):1281–1292.
  • Heinz WJ, Stanchi KMC, Klinker H, et al. Posaconazole plasma concentration in pediatric patients receiving antifungal prophylaxis after allogeneic hematopoietic stem cell transplantation. Med Mycol. 2016;54(2):128–137.
  • Boonsathorn S, Cheng I, Kloprogge F, et al. Clinical pharmacokinetics and dose recommendations for posaconazole in infants and children. Clin Pharmacokinet. 2019;58(1):53–61.
  • Döring M, Müller C, Johann PD, et al. Analysis of posaconazole as oral antifungal prophylaxis in pediatric patients under 12 years of age following allogeneic stem cell transplantation. BMC Infect Dis. 2012;12(1):263.
  • Arrieta AC, Sung L, Bradley JS, et al. A non-randomized trial to assess the safety, tolerability, and pharmacokinetics of posaconazole oral suspension in immunocompromised children with neutropenia. PLoS ONE. 2019;14(3):1–17.
  • Vanstraelen K, Colita A, Bica AM, et al. Pharmacokinetics of posaconazole oral suspension in children dosed according to body surface area. Pediatr Infect J. 2016;35(2):183–188.
  • Bernardo VA, Cross SJ, Crews KR, et al. Posaconazole therapeutic drug monitoring in pediatric patients and young adults with cancer. Ann Pharmacother. 2013;47(7–8):976–983.
  • Mathew S, Kussin ML, Liu D, et al. Retrospective analysis of posaconazole suspension dosing strategies in a pediatric oncology population: single-center experience. J Pediatr Infect Soc. 2017;6(3):e149–e151.
  • Wass EN, Hernandez EA, Sierra CM. Comparison of the efficacy of posaconazole delayed release tablets and suspension in pediatric hematology/ oncology patients. J Pediatr Pharmacol Ther. 2020;25:47–52.
  • Lambrix AA, Swanson HD, Pauley JL, et al. Experience using intravenous posaconazole in paediatric and young adult oncology patients. J Antimicrob Chemother. 2020;75(12):3682–3687.
  • Nickless JR, Bridger KE, Vora SB, et al. Evaluation of intravenous posaconazole dosing and pharmacokinetic target attainment in pediatric patients. J Pediatr Infect Soc. 2019;8(4):365–367.
  • Strommen A, Hurst AL, Curtis D, et al. Use of intravenous posaconazole in hematopoietic stem cell transplant patients. J Pediatr Hematol Oncol. 2018;40(4):e203–e206.
  • Jancel T, Shaw PA, Hallahan CW, et al. Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review. J Clin Pharm Ther. 2017;42(1):75–79.
  • Cesaro S, Milano G, Aversa F. Retrospective survey on the off-label use of posaconazole in pediatric hematology patients. Eur J Clin Microbiol Infect Dis. 2011;30(4):595–596.
  • Vicenzi EB, Calore E, Decembrino N, et al. Posaconazole oral dose and plasma levels in pediatric hematology-oncology patients. Eur J Haematol. 2018;100(3):315–322.
  • Patel D, Popple S, Claydon A, et al. Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease. Med Mycol. 2020;58(1):11–21.
  • Arikan K, Aytac S, Büyükcam A, et al. Is posaconazole really effective in adolescent patients as a prophylactic agent: experience of a tertiary care center. J Pediatr Hematol Oncol. 2021;43(5):e613–e618.
  • European Medicines Agency. Opinion of the paediatric committee on the acceptance of a modification of an agreed paediatric investigation plan (EMEA-000468-PIP02-12-M06). [Internet]. 2020. [cited 2021 Feb 20]. Available from: https://www.ema.europa.eu/en/documents/pip-decision/p/0101/2020-ema-decision-18-march-2020-acceptance-modification-agreed-paediatric-investigation-plan_en.pdf.
  • Courtney R, Sansone A, Smith W, et al. Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease. J Clin Pharmacol. 2005;45(2):185–192.
  • Hachem RY, Langston AA, Graybill JR, et al. Posaconazole as salvage treatment of invasive fungal infections in patients with underlying renal impairment. J Antimicrob Chemother. 2008;62(6):1386–1391.
  • Girmenia C. New generation azole antifungals in clinical investigation. Expert Opin Investig Drugs. 2009;18(9):1279–1295.
  • Kim S-H, Kwon J-C, Park C, et al. Therapeutic drug monitoring and safety of intravenous voriconazole formulated with sulfobutylether β‐cyclodextrin in haematological patients with renal impairment. Mycoses. 2016;59(10):644–651.
  • Moton A, Krishna G, Ma L, 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.
  • Sime FB, Byrne CJ, Parker S, et al. Population pharmacokinetics of total and unbound concentrations of intravenous posaconazole in adult critically ill patients. Crit Care. 2019;23(1):205–undefined.
  • Pyrpasopoulou A, Iosifidis E, Antachopoulos C, et al. Antifungal drug dosing adjustment in critical patients with invasive fungal infections. J Emerg Crit Care Med. 2019;3:37.
  • Jacinto PL, Chandrasekar P. Safety of posaconazole. Expert Opin Drug Saf. 2013;12(2):265–274.
  • Moton A, Krishna G, Wang Z. Tolerability and safety profile of posaconazole: evaluation of 18 controlled studies in healthy volunteers. J Clin Pharma Ther. 2009;34(3):301–311.
  • Chaftari AM, Hachem RY, Ramos E, et al. Comparison of posaconazole versus weekly amphotericin B lipid complex for the prevention of invasive fungal infections in hematopoietic stem-cell transplantation. Transplantation. 2012;94(3):302–308.
  • Chau MM, Kong DCM, Hal SJV, et al. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Int Med J. 2014;44(12b):1364–1388.
  • Chandrasekar P. Prophylaxis against Aspergillus is not perfect: problems and perils in stem cell transplantation. Med Mycol. 2009;47(s1):S349–54.
  • Felton TW, Baxter C, Moore CB, et al. Efficacy and safety of posaconazole for chronic pulmonary aspergillosis. Clin Infect Dis. 2010;51(12):1383–1391.
  • Raad II, Graybill JR, Bustamante AB, et al. Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections. Clin Infect Dis. 2006;42(12):1726–1734.
  • Perissinotti AJ, Marini BL. Managing liver dysfunction in haematology patients: switch antifungals, or use the tincture of time? Mycoses. 2019;62(3):214–216.
  • Pettit NN, Miceli MH, Rivera CG, et al. Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation. J Antimicrob Chemother. 2017;72(8):2355–2358.
  • Di Pippo AJ, Rausch CR, Kontoyiannis DP. Tolerability of isavuconazole after posaconazole toxicity in leukaemia patients. Mycoses. 2019;62(1):81–86.
  • Tverdek FP, Heo ST, Aitken SL, et al. Real-life assessment of the safety and effectiveness of the new tablet and intravenous formulations of posaconazole in the prophylaxis of invasive fungal infections via analysis of 343 courses. Antimicrob Agents Chemother. 2017;61(8):e00188–17.
  • Pettit N, Han Z, and De La Cruz J, et al. Posaconazole (PCZ) tablet formulation Therapeutic Drug Monitoring (TDM) and toxicity analysis. 54th Interscience Conference on Antimicrobrial Agents and Chemotherapy 5-9 September 2014 Washington, DC. ; 2014.
  • Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999;12(1):40–79.
  • Nivoix Y, Levêque D, Herbrecht R, et al. The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet. 2008;47(12):779–792.
  • Sansone-Parsons A, Krishna G, Martinho M, et al. Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus. Pharmacotherapy. 2007;27(6):825–834.
  • Krishna G, Moton A, Ma L, et al. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers. Clin Ther. 2009;31(2):286–298.
  • Neofytos D, Avdic E, and Magiorakos AP. Clinical safety and tolerability issues in use of triazole derivatives in management of fungal infections. Drug Heal Patient Sad. 2010; 2: ;27–38DOI:https://doi.org/10.2147/DHPS.S6321
  • Krishna G, Sansone-Parsons A, Kantesaria B. Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men. Curr Med Res Opin. 2007;23(6):1415–1422.
  • Courtney R, Wexler D, and Statkevich P. Effect of cimetidine on the pharmacokinetics of posaconazole in healthy volunteers. Thesis/Dissertation.Poster presented at:42nd Interscience Conference on Antimicrobial Agents and Chemotherapy September 27–30, 2002. San Diego, CA.
  • Cojutti P, Candoni A, Simeone E, et al. Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia: dose intensification coupled with avoidance of proton pump inhibitors is beneficial in shortening time to effective concentrations. Antimicrob Agents Chemother. 2013;57(12):6081–6084.
  • Krishna G, Parsons A, Kantesaria B, et al. Evaluation of the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy men. Curr Med Res Opin. 2007;23(3):545–552.
  • Sathiapalan RK, El-Solh H. Enhanced vincristine neurotoxicity from drug interactions: case report and review of literature. Pediatr Hematol Oncol. 2001;18(8):543–546.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.