A safety and feasibility study comparing an intermittent high dose with a daily standard dose of liposomal amphotericin B for persistent neutropenic fever Free

Abstract

A high intermittent dose regimen (group A: 10 mg kg on day 1, 5 mg kg on days 3 and 6) was compared with standard dosing (group B: 3 mg kg per day for 14 days) of liposomal amphotericin B (LAB) for empirical treatment of persistent febrile neutropenia. A total cumulative dose of 1275 mg (group A) and 2800 mg (group B) was administered. Infusion-related adverse drug events, mainly rigors/chills, occurred more frequently with group A (11/45, 24 % infusions) than with group B (12/201, 6 % infusions) (=0.002), which extended the mean infusion time by 20 min (=0.001). Creatinine levels were similar in the two regimens: the A : B ratio of the area under the curve for creatinine (AUC) for days 2–7 was 1.09 (=0.27) and for days 2–14 was 1.05 (=0.51). Rises in creatinine were mild (clinical toxicity criteria 1) in all patients with elevations. Hypokalaemia tended to be less severe in group A with a lower proportion of hypokalaemic days [57/143 (39 %) vs 80/137 (58 %), =0.21], a higher AUC (A : B ratio of 1.06, =0.12), a lower proportion of patients with hypokalaemia at the end of study (10 vs 61 %, =0.01) and fewer potassium-supplemented days [12/210 (6 %) vs 41/210 (19.5 %), <0.1]. There were mildly elevated median levels of serum bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, which were similar for the two regimens and were usually associated with other co-existing co-morbid conditions. The AUC for these enzymes was also similar in the two groups. No patient had discontinuation of the study drug due to toxicity. Composite success was identical for each regimen (11/15 patients, 73 %). Three of the fifteen patients in group B and none in group A developed invasive fungal infections (IFIs). --Glucan levels were similar in both groups for patients without an IFI [AUC of 362 and 683 (=0.36) for groups A and B, respectively]. The rate of defervescence was similar for each regimen (=0.75). This feasibility study suggests that a short intermittent high-dose course of 10/5/5 mg LAB kg on days 1, 3 and 6 may be as safe and effective as a standard 14 day course of 3 mg kg per day, with drug-acquisition cost savings and reduced drug exposure. A larger study is indicated for confirmation of this.

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2009-11-01
2024-03-28
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References

  1. Adler-Moore J., Proffitt R. T. 2003; Effect of tissue penetration on AmBisome efficacy. Curr Opin Investig Drugs 4:179–185
    [Google Scholar]
  2. Adler-Moore J. P., Proffitt R. T. 2008; Amphotericin B lipid preparations: what are the differences?. Clin Microbiol Infect 14 (Suppl. 4):25–36 [CrossRef]
    [Google Scholar]
  3. Adler-Moore J. P., Olson J. A., Proffitt R. T. 2004; Alternative dosing regimens of liposomal amphotericin B (AmBisome) effective in treating murine systemic candidiasis. J Antimicrob Chemother 54:1096–1102 [CrossRef]
    [Google Scholar]
  4. Bates D. W., Su L., Yu D. T., Chertow G. M., Seger D. L., Gomes D. R., Dasbach E. J., Platt R. 2001; Mortality and costs associated with amphotericin B therapy. Clin Infect Dis 32:686–693 [CrossRef]
    [Google Scholar]
  5. Bekersky I., Fielding R. M., Dressler D. E., Lee J. W., Buell D. N., Walsh T. J. 2002; Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother 46:828–833 [CrossRef]
    [Google Scholar]
  6. Camp M. J., Wingard J. R., Gilmore C. E., Lin L. S., Dix S. P., Davidson T. G., Geller R. B. 1998; Efficacy of low dose dopamine in preventing amphotericin B nephrotoxicity in bone marrow transplant patients and leukemia patients. Antimicrob Agents Chemother 42:3103–3106
    [Google Scholar]
  7. Clark A. D., McKendrick S., Tansey P. J., Franklin I. M., Chopra R. 1998; A comparative analysis of lipid-complexed and liposomal amphotericin B preparations in haematological oncology. Br J Haematol 103:198–204 [CrossRef]
    [Google Scholar]
  8. Coiffier B., Lepage E., Briere J., Herbrecht R., Tilly H., Bouabdallah R., Morel P., Van Den Neste E., Salles G. other authors 2002; CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242 [CrossRef]
    [Google Scholar]
  9. Collette N., Van der Auwera P., Meunier F., Lambert C., Sculier J. P., Coune A. 1991; Tissue distribution and bioactivity of amphotericin B administered in liposomes to cancer patients. J Antimicrob Chemother 27:535–548 [CrossRef]
    [Google Scholar]
  10. Cordonnier C., Mohty M., Faucher C., Vey N., Pautas C., Robin M., Mahi L., Ribaud P. 2005; Safety of a weekly administration of 10 mg/kg of liposomal amphotericin B for antifungal prophylaxis in allogeneic stem-cell transplant and acute leukemia patients. In American Society of Hematology 47th Annual Meeting10–13 December 2005 Atlanta, GA, USA: abstract 5346
    [Google Scholar]
  11. Cornely O. A., Maertens J., Bresnik M., Ebrahimi R., Ullmann A. J., Bouza E., Heussel C. P., Lortholary O., Rieger C. other authors 2007; Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiload Trial. Clin Infect Dis 44:1289–1297 [CrossRef]
    [Google Scholar]
  12. Coukell A. J., Brogden R. N. 1998; Liposomal amphotericin B: therapeutic use in the management of fungal infections and visceral leishmaniasis. Drugs 55:585–612 [CrossRef]
    [Google Scholar]
  13. Demartini G., Lequaglie C., Brega Messone P. P., Scaglione F., Fraschini F. 2005; Penetration of amphotericin B in human lung tissue after single liposomal amphotericin B (AmBisome) infusion. J Chemother 17:82–85 [CrossRef]
    [Google Scholar]
  14. De Pauw B., Walsh T. J., Donnelly J. P., Stevens D. A., Edwards J. E., Calandra T., Pappas P. G., Maertens J., Lortholary O. other authors 2008; Revised definitions of invasive fungal disease from the European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813–1821 [CrossRef]
    [Google Scholar]
  15. Deray G. 2002; Amphotericin B nephrotoxicity. J Antimicrob Chemother 49 (Suppl. 1):37–41 [CrossRef]
    [Google Scholar]
  16. El-Cheikh J., Faucher C., Furst S., Duran S., Berger P., Vey N., Stoppa A. M., Bouabdallah R. other authors 2007; High dose weekly liposomal amphotericin B antifungal prophylaxis following reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 39:301–306 [CrossRef]
    [Google Scholar]
  17. Ellis M. 2002; Invasive fungal infections: evolving challenges for diagnosis and therapeutics. Mol Immunol 38:947–957 [CrossRef]
    [Google Scholar]
  18. Ellis M. 2004; Preventing microbial translocation in haematological malignancy. Br J Haematol 125:282–293 [CrossRef]
    [Google Scholar]
  19. Ellis M. 2008; New dosing strategies for liposomal amphotericin B in high-risk patients. Clin Microbiol Infect 14 (Suppl. 4):55–64
    [Google Scholar]
  20. Ellis M. E., al-Hokail A., Clink H., Padmos A., Ernst P., Spence D. G., Tharpe W. N., Hillier V. F. 1992; Double blind randomized study of the effect of infusion rates on toxicity of amphotericin B. Antimicrob Agents Chemother 36:172–179 [CrossRef]
    [Google Scholar]
  21. Ellis M., Shamoon A., Gorka W., Zwaan F., al-Ramadi B. 2001; Severe hepatic injury associated with lipid formulations of amphotericin B. Clin Infect Dis 32:E87–E89 [CrossRef]
    [Google Scholar]
  22. Ellis M., Hedstrom U., al-Ramadi B., Alizadeh H., Kristensen J., Kshirsagar S., Blaschke T., Stevens D., Klingspor L., Poughias L. 2007; Pharmacokinetics, efficacy of 3mg/kg/day vs 10mg/kg day 1, 5 mg/kg days 3 and 6 liposomal amphotericin B (Ambisome) in febrile neutropenia. In 8th Congress of the European Association for Clinical Pharmacology and Therapeutics 29 August–1 September 2007, Amsterdam, the Netherlands, abstract P257
    [Google Scholar]
  23. Ellis M., al-Ramadi B., Finkelman M., Hedstrom U., Kristensen J., Ali-Zadeh H., Klingspor L. 2008; Assessment of the clinical utility of serial β -d-glucan concentrations in patients with persistent neutropenic fever. J Med Microbiol 57:287–295 [CrossRef]
    [Google Scholar]
  24. EORTC IATCG 1989; Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 86:668–672 [CrossRef]
    [Google Scholar]
  25. Eriksson U., Seifert B., Scaffner A. 2001; Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomized controlled trial. BMJ 322:579–582 [CrossRef]
    [Google Scholar]
  26. Farag S. S., Ruppert A. S., Mrozek K., Mayer R. J., Stone R. M., Carroll A. J., Powell B. L., Moore J. O., Pettanati M. J. other authors 2005; Outcome of induction and post-remission therapy in younger adults with acute myeloid leukemia with normal karyotype: a cancer and leukemia group study. J Clin Oncol 23:482–493
    [Google Scholar]
  27. Fleiss J., Levin B., Paik M. 2003 Statistical Methods for Rates and Proportions , 3rd edn. New York: Wiley Interscience;
    [Google Scholar]
  28. Francis P., Lee J. W., Hoffman A., Peter J., Francesconi A., Bacher J., Shelhamer J., Pizzo P. A., Walsh T. J. 1994; Efficacy of unilamellar liposomal amphotericin B in treatment of pulmonary aspergillosis in persistently granulocytopenic rabbits: the potential role of brochoalveolar d-mannitol and serum galactomannan as markers of infection. J Infect Dis 169:356–368 [CrossRef]
    [Google Scholar]
  29. Garbino J., Adam A. 2006; Use of high-dose liposomal amphotericin B: efficacy and tolerance. Acta Biomed 77 (Suppl. 4):19–22
    [Google Scholar]
  30. Garcia A., Adler-Moore J., Proffitt R. 2000; Single-dose AmBisome (liposomal amphotericin B) as prophylaxis for murine systemic candidiasis and histoplasmosis. Antimicrob Agents Chemother 44:2327–2332 [CrossRef]
    [Google Scholar]
  31. Garey K. W., Rege M., Pai M. P., Mingo D. E., Suda K. J., Turpin R. S., Bearden D. T. 2006; Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 43:25–31 [CrossRef]
    [Google Scholar]
  32. Goldberg E., Gafter-Gvili A., Robenshtok E., Leibovici L., Paul M. 2008; Empirical antifungal therapy for patients with neutropenia and persistent fever: systematic review and meta-analysis. Eur J Cancer 44:2192–2203 [CrossRef]
    [Google Scholar]
  33. Greene R. E., Schlamm H. T., Oestmann J. W., Stark P., Durand C., Lortholary O., Wingard J. R., Herbrecht R., Ribaud P. other authors 2007; Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis 44:373–379 [CrossRef]
    [Google Scholar]
  34. Gubbins P. O., Penzak S. R., Ploston S., McConnell S. A., Anaissie A. 2002; Characterizing and predicting amphotericin B-associated nephrotoxicity in bone marrow or peripheral blood stem cell transplant recipients. Pharmacotherapy 22:961–971 [CrossRef]
    [Google Scholar]
  35. Hughes W. T., Armstrong D., Bodey G. P., Bow E. J., Brown A. E., Calandra T., Feld R., Pizzo P. A., Rolston K. V. I. other authors 2002; 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730–751 [CrossRef]
    [Google Scholar]
  36. Kelsey S. M., Goldman J. M., McCann S., Newland A. C., Scarffe J. H., Oppenheim B. A., Mufti G. J. 1999; Liposomal amphotericin B (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomized, double-blind placebo-controlled study. Bone Marrow Transplant 23:163–168 [CrossRef]
    [Google Scholar]
  37. Klastersky J. 2004; Antifungal therapy in patients with fever and neutropenia – more rational and less empirical?. N Engl J Med 351:1445–1447 [CrossRef]
    [Google Scholar]
  38. Lanternier F., Lortholary O. 2008; Liposomal amphotericin B: what is its role in 2008?. Clin Microbiol Infect 14 (Suppl. 4):71–83 [CrossRef]
    [Google Scholar]
  39. Leenders A. C., Daenen S., Jansen R. L., Hop W. C., Lowenberg B., Wijermans P. W., Cornelissen J., Herbrecht R. other authors 1998; Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections. Br J Haematol 103:205–212 [CrossRef]
    [Google Scholar]
  40. Marr K. A. 2008; Primary antifungal prophylaxis in hematopoietic stem cell transplant recipients: clinical implications of recent studies. Curr Opin Infect Dis 21:409–414 [CrossRef]
    [Google Scholar]
  41. Masiá Canuto M. M., Gutiérrez Rodero F. 2002; Antifungal drug resistance to azoles and polyenes. Lancet Infect Dis 2:550–563 [CrossRef]
    [Google Scholar]
  42. MRC WPLA 2006; Medical Research Council Acute Lymphoblastic Leukemia Trial XII (UKALL XII), version 4.1, February 2006. Joint Trial with Eastern Cooperative Group (ECOG) – E2993. Protocol for adults with ALL. Modified for intrathecal therapy and Philadelphia Positive ALL July 2002 Revised May 2005, February 2006 http://www.ctsu.ox.ac.uk/projects/leuk/ukall2003
    [Google Scholar]
  43. Mehta P., Vinks A., Filipovitch A., Vaughan G., Fearing D., Sper C., Davies S. 2006; High dose weekly AmBisome antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study. Biol Blood Marrow Transplant 12:235–240 [CrossRef]
    [Google Scholar]
  44. Meunier F., Prentice H. G., Ringden O. 1991; Liposomal amphotericin B (AmBisome): safety data from a phase II/III clinical trial. J Antimicrob Chemother 28 (Suppl. B):83–91
    [Google Scholar]
  45. Mills W., Chopra R., Linch D. C., Goldstone A. H. 1994; Liposomal amphotericin B in the treatment of fungal infections in neutropenic patients: a single centre experience of 133 episodes in 116 patients. Br J Haematol 86:754–760 [CrossRef]
    [Google Scholar]
  46. Moen M. D., Lyseng-Williamson K. A., Scott L. J. 2009; Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections. Drugs 69:361–392 [CrossRef]
    [Google Scholar]
  47. NCI 1998 Common Toxicity Criteria , version 2.0 Bethesda, MD: National Cancer Institute; http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf
    [Google Scholar]
  48. Olson J. A., Adler-Moore J., Schwartz J., Jensen G., Proffitt R. 2006; Comparative efficacies, toxicities, and tissue concentrations of amphotericin B lipid formulations in a murine aspergillosis model. Antimicrob Agents Chemother 50:2122–2131 [CrossRef]
    [Google Scholar]
  49. Ostrosky-Zeichner L., Marr K. A., Rex J. H., Cohen S. H. 2003; Amphotericin B: time for a new ‘gold standard’. Clin Infect Dis 37:415–425 [CrossRef]
    [Google Scholar]
  50. Patterson T. F., Kirkpatrick W. R., White M., Hiemenz J. W., Wingard J. R., Dupont B., Rinaldi M. G., Stevens D. A., Graybill J. R. for the Aspergillus Study Group; 2000; Invasive aspergillosis: disease spectrum, treatment practices, and outcomes. Medicine (Baltimore 79:250–260 [CrossRef]
    [Google Scholar]
  51. Penack O., Schartz S., Martus P., Reinwald M., Schmidt-Hieber M., Thiel E., Blau I. W. 2006; Low dose liposomal amphotericin B in the prevention of invasive fungal infections in patients with prolonged neutropenia: results from a randomized single center trial. Ann Oncol 17:1306–1312 [CrossRef]
    [Google Scholar]
  52. Prentice H. G., Hann I. M., Herbrecht R., Aoun M., Kvaloy S., Catovsky D., Pinkerton C. R., Schey S. A., Jacobs F. other authors 1997; A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol 98:711–718 [CrossRef]
    [Google Scholar]
  53. Saliba F., Dupont B. 2008; Renal impairment and amphotericin B formulations in patients with invasive fungal infections. Med Mycol 46:97–112 [CrossRef]
    [Google Scholar]
  54. Smith P. J., Olson J. A., Constable D., Schwartz J., Proffitt R. T., Adler-Moore J. 2007; Effects of dosing regimen on accumulation, retention and prophylactic efficacy of liposomal amphotericin B. J Antimicrob Chemother 59:941–951 [CrossRef]
    [Google Scholar]
  55. Sobel J. D. 2006; Design of clinical trials of empiric antifungal therapy in patients with persistent febrile neutropenia: considerations and critiques. Pharmacotherapy 26:47S–54S [CrossRef]
    [Google Scholar]
  56. Takemoto K., Yamamoto Y., Ueda Y., Sumita Y., Yoshida K., Niki Y. 2006a; Comparative study on the efficacy of AmBisome and Fungizone in a mouse model of pulmonary aspergillosis. J Antimicrob Chemother 57:724–731 [CrossRef]
    [Google Scholar]
  57. Takemoto K., Yamamoto Y., Ueda Y. 2006b; Evaluation of antifungal pharmacodynamic characteristics of AmBisome against Candida albicans . Microbiol Immunol 50:579–586 [CrossRef]
    [Google Scholar]
  58. Townsend R. W., Zutshi A., Behersky I. 2001; Biodistribution of 4-[14C]cholesterol–AmBisome following a single intravenous administration to rats. Drug Metab Dispos 29:681–685
    [Google Scholar]
  59. Vogelsinger H., Weiler S., Djanani A., Kountchev J., Bellmann-Weiler R., Wiedermann C. J., Bellmann R. 2006; Amphotericin B distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion. J Antimicrob Chemother 57:1153–1160 [CrossRef]
    [Google Scholar]
  60. Walsh T. J., Finberg R. W., Arndt C., Hiemenz J., Schwartz C., Bodensteiner D., Pappas P., Seibel N., Greenberg R. N. other authors 1999; Liposomal amphotericin B for empirical therapy in patients with persisting fever and neutropenia. N Engl J Med 340:764–771 [CrossRef]
    [Google Scholar]
  61. Walsh T. J., Goodman J. L., Pappas P., Bekersky I., Buell D. N., Roden M., Barrett J., Anaissie A. J. 2001; Safety, tolerance and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother 45:3487–3496 [CrossRef]
    [Google Scholar]
  62. Walsh T. J., Pappas P., Winston D. J., Lazarus H. M., Petersen F., Raffalli J., Yanovich S., Stiff P., Greenberg R. other authors 2002; Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 346:225–234 [CrossRef]
    [Google Scholar]
  63. Walsh T. J., Teppler H., Donowitz G. R., Maertens J. A., Baden L. R., Dmoszynska A., Cornely O. A., Bourque M. R., Lupinacci R. J. other authors 2004; Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 351:1391–1402 [CrossRef]
    [Google Scholar]
  64. Wingard J. R., White M. H., Anaissie E., Raffalli J., Goodman J., Arrieta A. L. 2000; A randomized double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clin Infect Dis 31:1155–1163 [CrossRef]
    [Google Scholar]
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