Skip to main content
SpringerLink
Log in

Safety, Toxicokinetics and Tissue Distribution of Long-Term Intravenous Liposomal Amphotericin B (ambisome®): A 91-day Study in Rats

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated.

Methods. Rats (174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg), dextrose, or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated.

Results. Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] ≤51 mg/dl; creatinine unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma; kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues.

Conclusions. Despite nonlinear accumulation, AmBisome revealed predictable hepatic and renal toxicities after 91 days, with no new or delayed effects after prolonged treatment at high doses that resulted in plasma levels >200 μg/ml and tissue levels >3000 μg/g.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. I. Bekersky, R. M. Fielding, D. Buell, and I. Lawrence. Lipidbased amphotericin B formulations: from animals to man. Pharm. Sci. Technol. Today 2:230–236 (1999).

    Google Scholar 

  2. R. M. Fielding, A. W. Singer, L. H. Wang, S. Babbar, and L. S. S. Guo. Relationship of pharmacokinetics and tissue distribution to reduced toxicity of colloidal amphotericin B in dogs. Antimicrob. Agents Chemother. 36:299–307 (1992).

    Google Scholar 

  3. K. M. Wasan, A. L. Kennedy, S. M. Cassidy, et al. Pharmacokinetics, distribution in serum lipoproteins and tissues, and renal toxicities of amphotericin B and amphotericin B lipid complex in a hypercholesterolemic rabbit model: single-dose studies. Antimicrob. Agents Chemother. 42:3146–3152 (1998).

    Google Scholar 

  4. J. P. Sculier, A. Coune, F. Meunier. Pilot study of amphotericin B entrapped in sonicated liposomes in cancer patients with fungal infections. Eur. J. Cancer Clin. Oncol. 24:527–538 (1988).

    Google Scholar 

  5. G. Lopez-Berestein, V. Fainstein, R. Hopfer, et al. Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: A preliminary study. J. Infect. Dis. 151:704–710 (1985).

    Google Scholar 

  6. R. P. Rapp, P. O. Gubbins, and M. E. Evans. Amphotericin B lipid complex. Ann. Pharmacother. 31:1174–86 (1997).

    Google Scholar 

  7. R. T. Proffitt, A. Satorius, S.-M. Chiang. Pharmacology and toxicology of a liposomal formulation of amphotericin B (AmBisome) in rodents. J. Antimicrob. Chemother. 28(suppl. B):49–61 (1991).

    Google Scholar 

  8. K. V. Clemons and D. A. Stevens. Therapeutic efficacy of a liposomal formulation of amphotericin B (AmBisome) against murine blastomycosis. J. Antimicrob. Chemother. 32:465–472 (1993).

    Google Scholar 

  9. T. J. Walsh, V. Yeldandi, M. McEvoy. Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients. Antimicrob. Agents Chemother. 42:2391–2398 (1998).

    Google Scholar 

  10. T. J. Walsh, R. W. Finberg, C. Arndt. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. New Engl. J. Med. 340:764 (1999).

    Google Scholar 

  11. J. R. Wingard, M. H. White, E. J. Anaissie. A randomized double-blind safety study of AmBisome and Abelcet in febrile neutropenic patients. 9th Focus on Fungal Infections Meeting, March 1999, San Diego, CA, Abstr. 15.

  12. I. Bekersky, D. Buell, M. Tomishima, K. Maki, I. Lawrence, and R. M. Fielding. New approaches to systemic antifungal therapy: Case studies of AmBisome and FK463. Recent Res. Devel. Antimicrob. Agents Chemother. 3:407–413 (1999).

    Google Scholar 

  13. A. J. Coukell and R. N. Brogden. Liposomal amphotericin B: Therapeutic use in the management of fungal infections and visceral leishmaniasis. Drugs 55:585–612 (1998).

    Google Scholar 

  14. G. W. Boswell, D. Buell, and I. Bekersky. AmBisome (liposomal amphotericin B): a comparative review. J. Clin. Pharmacol. 38: 583–592 (1998).

    Google Scholar 

  15. T. J. Walsh, E. J. Anaissie, J. L. Goodman. High-dose liposomal amphotericin B in patients infected with aspergillosis and other filamentous fungi. In Abstracts 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, Washington, DC, 1999, p. 573.

    Google Scholar 

  16. G. W. Boswell, I. Bekersky, D. Buell, R. Hiles, and T. J. Walsh. Toxicological profile and pharmacokinetics of a unilamellar liposomal vesicle formulation of amphotericin B in rats. Antimicrob. Agents Chemother. 42:263–268 (1998).

    Google Scholar 

  17. I. Bekersky, G. W. Boswell, R. Hiles, R. M. Fielding, D. Buell, and T. J. Walsh. Safety and toxicokinetics of intravenous liposomal amphotericin B (AmBisome) in Beagle dogs. Pharm. Res. 16:1694–1701(1999).

    Google Scholar 

  18. R. M. Fielding, R. O. Lewis, and L. Moon-McDermott. Altered tissue distribution and elimination of amikacin encapsulated in unilamellar, low-clearance liposomes (MiKasome®). Pharm. Res., 15:1775–1781 (1998).

    Google Scholar 

  19. A. Alak, S. Moys, and I. Bekersky. A high-performance liquid chromatographic assay for the determination of amphotericin B serum concentrations after the administration of AmBisome, a liposomal amphotericin B formulation. Ther. Drug Monit. 18: 604–609 (1996).

    Google Scholar 

  20. A. C. Parekh, R. J. Creno, and C. V. Dave. Hypercholesterolemic effect of amphotericin B: an analytical approach. Res. Commun. Chem. Pathol. Pharmacol. 9:307–314 (1974).

    Google Scholar 

  21. A. D. Dayan and P. K. Working. Non-clinical studies of the efficacy, pharmacokinetics and safety of amphotericin B colloidal dispersion (ABCD). Round Table Ser. R. Soc. Med. Press 32:12–26 (1994).

    Google Scholar 

  22. P. Longuet, V. Joly, P. Amirault, N. Seta, C. Carbon, and P. Yeni. Limited protection by small unilamellar liposomes against the renal tubular toxicity induced by repeated amphotericin B infusions in rats. Antimicrob. Agents Chemother. 35:1303–1308 (1991).

    Google Scholar 

  23. P. K. Working, M. S. Newman, T. Sullivan, M. Brunner, M. Podell, Z. Sahenk, and N. Turner. Comparative intravenous toxicity of cisplatin solution and cisplatin encapsulated in longcirculating, pegylated liposomes in cynomolgus monkeys. Toxicol. Sci. 46:155–165 (1998).

    Google Scholar 

  24. R. M. Fielding, G. Mukwaya, and R. A. Sandhaus. Clinical and preclinical studies with low-clearance liposomal Amikacin (Mi-Kasome). In M. C. Woodle and G. Storm (eds.), Long-Circulating Liposomes: Old Drugs, New Therapeutics, Springer-Verlag, Berlin, 1998, pp. 213–225.

    Google Scholar 

  25. J. P. Tolins and L. Raij. Chronic amphotericin B nephrotoxocity in the rat: Protective effect of calcium channel blockade. J. Am. Soc. Nephrol. 2:98–102 (1991).

    Google Scholar 

  26. L. H. Wang, R. M. Fielding, P. C. Smith, and L. S. S. Guo. Comparative tissue distribution and elimination of amphotericin B colloidal dispersion (Amphocil) and Fungizone after repeated dosing in rats. Pharm. Res. 12:275–283 (1995).

    Google Scholar 

  27. H.-H. Chow, Y. Cai, and M. Mayersohn. Disposition kinetics of amphotericin B in rats, the influence of dose. Drug Metab. Disp. 20:432–435 (1992).

    Google Scholar 

  28. R. M. Fielding, P. C. Smith, L. H. Wang, J. Porter, and L. S. S. Guo. Comparative pharmacokinetics of amphotericin B after administration of a novel colloidal delivery system, ABCD, and a conventional formulation to rats. Antimicrob. Agents Chemother. 35:1208–1213 (1991).

    Google Scholar 

  29. H. Ellens, E. Mayhew, and Y. M. Rustum. Reversible depression of the reticuloendothelial system by liposomes. Biochim. Biophys. Acta 714:479–485 (1982).

    Google Scholar 

  30. H. Harashima and H. Kiwada. Liposomal targeting and drug delivery: kinetic consideration. Adv. Drug Deliv. Rev. 19:425–444 (1996).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Fujisawa Healthcare Inc., Deerfield, IL

    Ihor Bekersky

  2. Calvert Preclinical Services, Olyphant, PA

    Garry W. Boswell

  3. Amylin Pharmaceuticals, Inc., San Diego, CA

    Richard Hiles

  4. Biologistic Services, Boulder, CO

    Robert M. Fielding

  5. Fujisawa Healthcare Inc., Deerfield, IL

    Donald Buell

  6. lmmunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD

    Thomas J. Walsh

Authors
  1. Ihor Bekersky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Garry W. Boswell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard Hiles
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert M. Fielding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donald Buell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas J. Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bekersky, I., Boswell, G.W., Hiles, R. et al. Safety, Toxicokinetics and Tissue Distribution of Long-Term Intravenous Liposomal Amphotericin B (ambisome®): A 91-day Study in Rats. Pharm Res 17, 1494–1502 (2000). https://doi.org/10.1023/A:1007605024942

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007605024942

Search

Navigation