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Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs

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Abstract

Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses.

Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology.

Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable.

Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18−94 µg/mL.

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REFERENCES

  1. J. E. Bennett. Antimicrobial Agents: Antifungal Agents. In J. G. Hardman and L. E. Limbird (eds.), Goodman & Gilman's the Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, New York, 1996, Ch. 49.

    Google Scholar 

  2. D. B. Bhathena, W. E. Bullock, C. E. Nuttall, and R. G. Luke. The effects of amphotericin B therapy on the intrarenal vasculature and renal tubules in man. Clin. Nephrol. 9:103–110 (1978).

    Google Scholar 

  3. I. Bekersky, R. M. Fielding, D. Buell, and I. Lawrence. Lipid-based amphotericin B formulations: from animals to man. Pharmaceut. Sci. Technol. Today 2:230–236 (1999).

    Google Scholar 

  4. 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 

  5. G. Lopez-Berestein, R. Mehta, R. L. Hopfer, et al. Treatment and prophylaxis of disseminated infection due to Candida albicans in mice with liposome encapsulated amphotericin B. J. Infect. Dis. 147:939–945 (1983).

    Google Scholar 

  6. J. Graybill, P. Craven, R. Taylor, D. Williams, and W. Magee. Treatment of murine cryptococcosis with liposome-associated amphotericin B. J. Infect. Dis. 145:748–752 (1982).

    Google Scholar 

  7. C. Tremblay, M. Barza, C. Fiore, and F. Szoka. Efficacy of liposome intercalated amphotericin B in the treatment of systemic candidiasis in mice. Antimicrob. Agents Chemother. 26:170–17 (1984).

    Google Scholar 

  8. 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 

  9. J. P. Sculier, A. Coune, F. Meunier, et al. 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 

  10. 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 

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

    Google Scholar 

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

    Google Scholar 

  13. J. P. Adler-Moore, S.-M. Chiang, A. Satorius, et al. Treatment of murine candidosis and ctyptococcosis with a unilamellar liposomal amphotericin B formulation (AmBisome). J. Antimicrob. Chemother. 28(Suppl. B):63–71 (1991).

    Google Scholar 

  14. 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 

  15. T. J. Walsh, V. Yeldandi, M. McEvoy, et al. 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 

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

    Google Scholar 

  17. 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 

  18. R. Janknegt, S. deMarie, I. A. J. M. Bakker-Woudenberg, et al. Liposomal and lipid formulations of amphotericin B: clinical pharmacokinetics. Clin. Pharmacokinet. 23:279–291 (1992).

    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. R. M. Fielding, G. Mukwaya, and R. A. Sandhaus. Clinical and preclinical studies with low-clearance liposomal Amikacin (MiKasome®). In M. C. Woodle and G. Storm (eds.), Long-Circulating Liposomes: Old Drugs, New Therapeutics, Springer-Verlag, New York, 1998, Ch. 15.

    Google Scholar 

  21. P. D. Hoeprich, A. C. Huston, and B. M. Wolfe. Toxicity of Amphotericins on Chronic Administration to Mongrel Dogs. Diagn. Microbiol. Infect. Dis. 3:47–58 (1985).

    Google Scholar 

  22. J. P. Adler-Moore and R. T. Proffitt. Development, characterization, efficacy and mode of action of AmBisome, a unilamellar liposomal formulation of amphotericin B. J. Liposome Res. 3:429–450 (1993).

    Google Scholar 

  23. 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 

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

    Google Scholar 

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Authors and Affiliations

  1. Fujisawa Healthcare Inc., 3 Parkway North, Deerfield, Illinois, 60015-2548

    Ihor Bekersky & Donald Buell

  2. MDS Harris Laboratories, Lincoln, Nebraska

    Garry W. Boswell

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

    Richard Hiles

  4. Biologistic Services, Boulder, Colorado

    Robert M. Fielding

  5. Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland

    Thomas J. Walsh

Authors
  1. Ihor Bekersky
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  2. Garry W. Boswell
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  3. Richard Hiles
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  4. Robert M. Fielding
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  5. Donald Buell
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  6. Thomas J. Walsh
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Correspondence to Ihor Bekersky.

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Bekersky, I., Boswell, G.W., Hiles, R. et al. Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs. Pharm Res 16, 1694–1701 (1999). https://doi.org/10.1023/A:1018997730462

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