Clinical Pharmacokinetics

, Volume 23, Issue 4, pp 279–291 | Cite as

Liposomal and Lipid Formulations of Amphotericin B

Clinical Pharmacokinetics
  • Robert Janknegt
  • Siem de Marie
  • Irma A. J. M. Bakker-Woudenberg
  • Daan J. A. Crommelin
Review Article Drug Disposition


Amphotericin B remains a very important drug for the treatment of fungal infections despite its toxicity. Encapsulation of amphotericin B into liposomes appears to reduce the toxic effects and to improve the clinical efficacy, allowing higher dosages to be given. The exact mechanism behind the reduced toxicity is not yet known.

Amphotericin B is widely distributed after intravenous administration as the deoxycholate solubilisate. The highest concentrations are found in the liver, spleen and kidney. Protein binding and binding to the tissues is very high. The fate of the drug in the body is not known in detail. Renal and biliary excretion are both low and no metabolites have been identified. The drug is still detectable in the liver, spleen and kidney for as long as 1 year after stopping therapy.

The pharmacokinetics of the different liposomal amphotericin B or lipid complexes of amphotericin B, which were recently developed, are quite diverse. A number of these preparations, such as amphotericin B lipid complex (ABLC), ‘AmBisome’ and amphotericin B colloidal dispersion (ABCD) are in clinical development. Their pharmacokinetics depend to a large extent on the composition and particle size of the liposomes or lipid complexes. Relatively large structures such as ABLC are rapidly taken up by the mononuclear phagocyte system, whereas smaller liposomes remain in the circulation for prolonged periods. In all studies only the total amphotericin B (both free and liposome- or lipid-associated) concentrations were determined.

There is a need for studies correlating clinical efficacy and tolerability of liposomal amphotericin B with the pharmacokinetic properties of these formulations.


Clinical Pharmacokinetic Acquire Immune Deficiency Syndrome Liposomal Amphotericin Lipid Complex Mononuclear Phagocyte System 
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  1. Ahmad I, Sarkar AK, Bachhawat BK. Effect of cholesterol in various liposomal compositions on the in vivo toxicity, therapeutic efficacy and tissue distribution of amphotericin B. Biotechnology and Applied Biochemistry 12: 550–556, 1990PubMedGoogle Scholar
  2. Atkinson AJ, Bennett JE. Amphotericin B pharmacokinetics in humans. Antimicrobial Agents and Chemotherapy 13: 271–276, 1978PubMedCrossRefGoogle Scholar
  3. Barriere SL. Pharmacology and pharmacokinetics of traditional systemic antifungal agents. Pharmacotherapy 10 (Suppl.): 134–140, 1990Google Scholar
  4. Benson JM, Nahata MC. Clinical use of systemic antifungal agents. Clinical Pharmacy 7: 424–438, 1988PubMedGoogle Scholar
  5. Chopra R, Blair S, Strang J, Patterson KG, Goldstone AH. Liposomal amphotericin B (AmBisome) in the treatment of fungal infections in neutropenic patients. Journal of Antimicrobial Chemotherapy 28: 93–104, 1991PubMedCrossRefGoogle Scholar
  6. Christiansen KJ, Bernard EM, Gold JW, Armstrong DA. Distribution and activity of amphotericin B in humans. Journal of Infectious Diseases 152: 1037–1043, 1985PubMedCrossRefGoogle Scholar
  7. Clark JM, Whitney RR, Olsen SJ, George RJ, Swerdel MR, et al. Amphotericin B lipid complex therapy of experimental fungal infections in mice. Antimicrobial Agents and Chemotherapy 35: 615–621, 1991PubMedCrossRefGoogle Scholar
  8. Clemons KV, Stevens DA. Comparative efficacy of amphotericin B colloidal dispersion and amphotericin B deoxycholate suspension in treatment of murine coccidioidomycosis. Antimicrobial Agents and Chemotherapy 35: 1829–1833, 1991PubMedCrossRefGoogle Scholar
  9. Colette N, Van der Auwera P, Meunier F, Lambert C, Sculier JP, et al. Tissue distribution and bioactivity of amphotericin B administered in liposomes to cancer patients. Journal of Antimicrobial Chemotherapy 27: 535–548, 1991CrossRefGoogle Scholar
  10. Coune A. Liposomes as drug delivery system in the treatment of infectious disease, potential applications and clinical experience. Infection 16: 141–147, 1988PubMedCrossRefGoogle Scholar
  11. Daneshmend TK, Warnock DW. Clinical pharmacokinetics of systemic antifungal drugs. Clinical Pharmacokinetics 8: 17–42, 1983PubMedCrossRefGoogle Scholar
  12. De Wit S, Rossi C, Duchateau J, Braitman A, Gupta R, et al. Safety, tolerance and immunomodulatory effect of amphotericin B lipid complex in HIV infected subjects. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 29–October 2, 1991. Abstract no. 288, p. 147, 1991Google Scholar
  13. Ellis ME, Al-Hokail AA, Clark HM. A study of rapid vs slow infusion of amphotericin B on toxicity, tolerance and efficacy. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 29–October 2, 1991. Abstract no. 744, p. 223, 1991Google Scholar
  14. Fielding RM. Liposomal drug delivery: advantages and limitations from a clinical pharmacokinetic and therapeutic perspective. Clinical Pharmacokinetics 21: 155–164, 1991PubMedCrossRefGoogle Scholar
  15. Fielding RM, Singer AW, Wang LH, Babbar S, Guo LS. Relationship of pharmacokinetics and drug disposition in tissue to increased safety of amphotericin B colloidal dispersion in dogs. Antimicrobial Agents and Chemotherapy 36: 299–307, 1992PubMedCrossRefGoogle Scholar
  16. Fielding RM, Smith PC, Wang LH, Porter J, Guo LS. Comparative pharmacokinetics of amphotericin B after administration of a novel colloidal delivery system, ABCD, and a conventional formulation to rats. Antimicrobial Agents and Chemotherapy 35: 1208–1213, 1991PubMedCrossRefGoogle Scholar
  17. Gondal JA, Swartz RP, Rahman A. Therapeutic evaluation of free and liposome-encapsulated amphotericin B in the treatment of systemic candidiasis in mice. Antimicrobial Agents and Chemotherapy 33: 1544–1548, 1989PubMedCrossRefGoogle Scholar
  18. Graybill JR, Sharkey PK, Vincent D, Johnson E, Havard PF, et al. Amphotericin B lipid complex in treatment of cryptococcal meningitis in patients with AIDS. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 29–October 2, 1991. Abstract no. 289, p. 147, 1991Google Scholar
  19. Gregoriadis G (Ed.) Liposome technology, Vols 1–3, CRC Press, Boca Raton, 1984Google Scholar
  20. Gregoriadis G (Ed.) Liposomes as drug carriers: recent trends and progress, J Wiley and Sons, Chichester, 1988Google Scholar
  21. Guo LG, Fielding RM, Gantz DL, Steiner J, Small DM. Structure of amphotericin B colloidal dispersion: a novel amphotericin B dosage form. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 29–October 2, 1991. Abstract no. 221, p. 135, 1991Google Scholar
  22. Guo LSS, Fielding RM, Lasic DD, Hamilton RL, Mufson D. Novel antifungal drug delivery: stable amphotericin B-cholesteryl sulfate discs. International Journal of Pharmaceutics 75: 45–51, 1991CrossRefGoogle Scholar
  23. Harrison LH, Stevens DA. Comparison of antifungal activity of amphotericin B deoxycholate suspension with that of amphotericin B sulfate colloidal dispersion. Antimicrobial Agents and Chemotherapy 36: 486–488, 1992CrossRefGoogle Scholar
  24. Hoeprich PD. Elimination half-life of amphotericin B. Journal of Infection 20: 173–175, 1990PubMedCrossRefGoogle Scholar
  25. Hopfer RL, Mehta R, Lopez-Berestein G. Synergistic antifungal activity and reduced toxicity of liposomal amphotericin B combined with Gramicidin S or NF. Antimicrobial Agents and Chemotherapy 31: 1978–1981, 1987PubMedCrossRefGoogle Scholar
  26. Holleran WM, Wilbur JR, DeGregorio MW. Empiric amphotericin B therapy in patients with acute leukemia. Reviews of Infectious Diseases 7: 619–624, 1985PubMedCrossRefGoogle Scholar
  27. Hwang KJ, Padki MM, Chow DC, Essien HE, Lai JY, et al. Uptake of small liposomes by non-reticuloendothelial tissues. Biochimica et Biophysica Acta 901; 88–96, 1987PubMedCrossRefGoogle Scholar
  28. Janknegt R, Paulissen A, Hooymans PM, Lohman JJ, Hermens WA. Stability of amphotericin B in CAPD fluid. Peritoneal Dialysis International 10: 287–289, 1990PubMedGoogle Scholar
  29. Janoff AS. Liposomes and lipid structures as carriers of amphotericin B. European Journal of Clinical Microbiology and Infectious Diseases 9: 146–151, 1990Google Scholar
  30. Joly V, Bolard J, Saint-Julien L, Carbon C, Yeni P. Influence of phospholipid/amphotericin B ratio and phospholipid type on in vitro renal cell toxicities and fungicidal activities of lipid-associated amphotericin B formulation. Antimicrobial Agents and Chemotherapy 36: 262–266, 1992PubMedCrossRefGoogle Scholar
  31. Juliano RL, Grant CW, Barber KR, Kalp MA. Mechanism of the selective toxicity of amphotericin B incorporated into liposomes. Molecular Pharmacology 31: 1–11, 1987PubMedGoogle Scholar
  32. Kan V, Bennett J, Amanthea M, Smolskis M, Grasela D, et al. Comparative safety and pharmacokinetic study of amphotericin B lipid complex and amphotericin B deoxycholate in healthy young male volunteers. Journal of Infectious Diseases 164: 418–425, 1991PubMedCrossRefGoogle Scholar
  33. Katz NM, Pierce PF, Anzeck RA, Visner MS, Canter HG, et al. Liposomal amphotericin B for treatment of pulmonary aspergillosis in a heart transplant patient. Journal of Heart Transplantation 9: 14–17, 1990PubMedGoogle Scholar
  34. Knight CG (Ed.) Liposomes: from physical structure to therapeutic applications, Elsevier, Amsterdam, 1981Google Scholar
  35. Lasic DD, Martin FJ, Gabizon A, Huang SK, Papahadjopoulos D. Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochimica Biophysica Acta, in press, 1992Google Scholar
  36. Lichtenberg D, Barenholz Y. Liposomes: preparation, characterization and preservation. Methods in Biochemical Analysis 33: 337–462, 1988CrossRefGoogle Scholar
  37. Llanos-Cuentas A, Chang J, Cieza I, Echevarria J, Garcia P, et al. Safety and tolerance of amphotericin B lipid complex vs Fungizone in patients with mucocutaneous leishmaniasis. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21–24, 1990. Abstract no. 568, p. 181, 1990Google Scholar
  38. Lopez-Berestein G, Bodey GP, Frankel LS, Mehta K. Treatment of hepatosplenic candidiasis with liposomal amphotericin B. Journal of Clinical Oncology 5: 310–317, 1987PubMedGoogle Scholar
  39. Lopez-Berestein G, Bodey GP, Fainstein V, Keating M, Frankel LS, Zeluff B, et al. Treatment of systemic fungal infections with liposomal amphotericin B. Archives of Internal Medicine 149: 2533–2536, 1989PubMedCrossRefGoogle Scholar
  40. Lopez-Berestein G, Fainstein V, Hopfer R, Mehta K, Sullivan MP, et al. Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: a preliminary study. Journal of Infectious Diseases 151: 704–710, 1985PubMedCrossRefGoogle Scholar
  41. Lopez-Berestein G, Kasi L, Rosenblum MG, et al. Clinical pharmacology of 99mTc labeled liposomes in patients with cancer. Cancer Research 44: 375–378, 1984PubMedGoogle Scholar
  42. Lopez-Berestein G, Mehta R, Hopfer RL, et al. Treatment and prophylaxis of disseminated infection due to Candida albicans in mice with liposome-encapsulated amphotericin B. Journal of Infectious Diseases 147: 939–945, 1983PubMedCrossRefGoogle Scholar
  43. Mehta R, Lopez-Berestein G, Hopfer R, Mills K, Juliano RL. Liposomal amphotericin B is toxic to fungal cells but not to mammalian cells. Biochimica et Biophysica Acta 770: 230–234, 1984PubMedCrossRefGoogle Scholar
  44. Meunier F, Prentice HG, Ringden O. Liposomal amphotericin B (AmBisome): safety data from a phase II/III clinical trial. Journal of Antimicrobial Chemotherapy 28: 83–91, 1991PubMedCrossRefGoogle Scholar
  45. Meunier F, Sculier JP, Coune A, Brassinne C, Heymans C, et al. Amphotericin B encapsulated in liposomes administered to cancer patients. Annals of the New York Academy of Sciences 544: 598–610, 1988PubMedCrossRefGoogle Scholar
  46. Morgan DJ, Ching MS, Raymond K, Bury RW, Mashford ML, et al. Elimination of amphotericin B in impaired renal function. Clinical Pharmacology and Therapeutics 34: 248–253, 1983PubMedCrossRefGoogle Scholar
  47. Naessander UK, Storm G, Peeters PA, Crommelin DJ. Liposomes. In Chasin & Langer (Eds) Biodegradable polymers as drug delivery systems, Chapter 8, pp. 261–338, Marcel Dekker Inc., New York, 1990Google Scholar
  48. New RPC. Liposomes: a practical approach. IRL Press, Oxford, 1990Google Scholar
  49. Ostro MJ, Cullis PR. Use of liposomes as injectable drug delivery systems. American Journal of Hospital Pharmacy 46: 1576–1587, 1989PubMedGoogle Scholar
  50. Powderly WG, Kobayashi GS, Herzig GP, Medoff G. Amphotericin B resistant yeast infection in severely immunocompromised patients. American Journal of Medicine 84: 826–832, 1988PubMedCrossRefGoogle Scholar
  51. Proffitt RT, Satorius A, Chiang SM, Sullivan L, Adler-Moore JP. Pharmacology and toxicology of a liposomal formulation of amphotericin B (AmBisome) in rodents. Journal of Antimicrobial Chemotherapy 28 (Suppl. B): 49–61, 1991PubMedCrossRefGoogle Scholar
  52. Ringden O, Meunier F, Tollemar J. Efficacy of amphotericin B (AmBisome) in the treatment of invasive fungal infections in immunocompromised patients. Journal of Antimicrobial Chemotherapy 28: 73–82, 1991PubMedCrossRefGoogle Scholar
  53. Sanders SW, Buchi KN, Goddard MS, Lang JK, Tolman KG. Single-dose pharmacokinetics and tolerance of a cholesterylsulfate complex of amphotericin B administered to healthy volunteers. Antimicrobial Agents and Chemotherapy 35: 1029–1034, 1991PubMedCrossRefGoogle Scholar
  54. Scherphof G, Roerdinch F, Waite M. Disintegration of phosphatidylcholine liposomes in plasma as a result of interaction with high density lipoproteins. Biochimica et Biophysica Acta 542: 296–302, 1978PubMedCrossRefGoogle Scholar
  55. Sculier JP, Bron A, Coune A, Meunier F. Successful treatment with liposomal amphotericin B in two patients with persisting fungemia. European Journal of Clinical Microbiology and Infectious Diseases 8: 903–907, 1989bCrossRefGoogle Scholar
  56. Sculier JP, Coune A, Meunier F, Brassinne C, Laduron C, et al. Pilot study of amphotericin B entrapped in sonicated liposomes in cancer patients with fungal infections. European Journal of Cancer and Clinical Oncology 24: 527–538, 1988CrossRefGoogle Scholar
  57. Sculier JP, Delcroix C, Brassinne C, Laduron C, Hollaert C, et al. Pharmacokinetics of amphotericin B in patients receiving repeated intravenous doses of amphotericin B entrapped into sonicated liposomes. Journal of Liposome Research 1: 151–166, 1989aCrossRefGoogle Scholar
  58. Senior JH. Fate and behaviour of liposomes in vivo, a review of controlling factors. Critical Reviews in Therapeutic Drug Carrier Systems 3: 123–93, 1987PubMedGoogle Scholar
  59. Sharkey PK, Lipke R, Renteria A, Galgiani J, Catanzaro A, et al. Amphotericin B lipid complex in treatment of coccidioidomycosis. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 29–October 2, 1991. Abstract no. 742, p. 222, 1991Google Scholar
  60. Storm G, Oussoren C, Peeters PAM. Safety of liposome administration. In Vigo-Pelfrey C (Ed.) Membrane lipid oxidation, Vol. III, pp. 239–263, CRC Press, Boca Raton, 1991Google Scholar
  61. Tollemar J, Ringden O, Tyden G. Liposomal amphotericin B (AmbiSome) treatment in solid organ and bone marrow transplant recipients: efficacy and safety evaluation. Clinical Transplantation 4: 167–176, 1990Google Scholar
  62. Van Etten EWM, Van de Rhee NE, Van Kampen M, Bakker-Woudenberg IAJM. Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans. Antimicrobial Agents and Chemotherapy 35: 2275–2281, 1991PubMedCrossRefGoogle Scholar
  63. Van’t Wout JW, Mattie H, Van Furth R. Comparison of the efficacies of amphotericin B, fluconzole, and itraconazole against a systemic Candida albicans infection in normal and neutropenic mice. Antimicrobial Agents and Chemotherapy 33: 147–151, 1989CrossRefGoogle Scholar
  64. Wasan KM, Vadiei, Lopez-Berestein G, Luke DR. Pharmacokinetics, tissue distribution and toxicity of free and liposomal amphotericin B in diabetic rats. Journal of Infectious Diseases 161: 562–566, 1990PubMedCrossRefGoogle Scholar
  65. Weber RS, Lopez-Berestein G. Treatment of invasive aspergillus sinusitis with liposomal amphotericin B. Laryngoscope 97: 937–941, 1987PubMedCrossRefGoogle Scholar
  66. Wiebe VJ, DeGregorio MW. Liposome-encapsulated amphotericin B: a promising new treatment for disseminated fungal infections. Reviews of Infectious Diseases 10: 1097–1101, 1988PubMedCrossRefGoogle Scholar
  67. Zonneveld G, Crommelin DJA. Liposomes: parenteral administration to man. In Gregoriadis G (Ed.) Liposomes as drug carriers: recent trends and progress, J Wiley and Sons, Chichester, 1988Google Scholar

Copyright information

© Adis International Limited 1992

Authors and Affiliations

  • Robert Janknegt
    • 1
    • 2
    • 3
  • Siem de Marie
    • 1
    • 2
    • 3
  • Irma A. J. M. Bakker-Woudenberg
    • 1
    • 2
    • 3
  • Daan J. A. Crommelin
    • 1
    • 2
    • 3
  1. 1.Department of Clinical PharmacyMaasland HospitalSittardThe Netherlands
  2. 2.Department of Clinical MicrobiologyAcademic Hospital Rotterdam DijkzigtRotterdamThe Netherlands
  3. 3.Faculty of Pharmacy, Department of PharmaceuticsUniversity of UtrechtUtrechtThe Netherlands

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