Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1997 Oct;41(10):2201–2208. doi: 10.1128/aac.41.10.2201

Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies.

A Adedoyin 1, J F Bernardo 1, C E Swenson 1, L E Bolsack 1, G Horwith 1, S DeWit 1, E Kelly 1, J Klasterksy 1, J P Sculier 1, D DeValeriola 1, E Anaissie 1, G Lopez-Berestein 1, A Llanos-Cuentas 1, A Boyle 1, R A Branch 1
PMCID: PMC164093  PMID: 9333048

Abstract

Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examined in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concentration performed by high-pressure liquid chromatography. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger volume of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and volume of distribution were increased with dose, peak and trough concentrations after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estimated half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concentrations in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.

Full Text

The Full Text of this article is available as a PDF (189.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen T. M., Hansen C. Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim Biophys Acta. 1991 Sep 30;1068(2):133–141. doi: 10.1016/0005-2736(91)90201-i. [DOI] [PubMed] [Google Scholar]
  2. Collette N., van der Auwera P., Lopez A. P., Heymans C., Meunier F. Tissue concentrations and bioactivity of amphotericin B in cancer patients treated with amphotericin B-deoxycholate. Antimicrob Agents Chemother. 1989 Mar;33(3):362–368. doi: 10.1128/aac.33.3.362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Gates C., Pinney R. J. Amphotericin B and its delivery by liposomal and lipid formulations. J Clin Pharm Ther. 1993 Jun;18(3):147–153. doi: 10.1111/j.1365-2710.1993.tb00605.x. [DOI] [PubMed] [Google Scholar]
  4. Goto R., Ibuki Y. Tissue distribution of liposomes prepared from synthetic amphiphiles after intraperitoneal injection into mice. Appl Radiat Isot. 1994 Jan;45(1):57–62. doi: 10.1016/0969-8043(94)90148-1. [DOI] [PubMed] [Google Scholar]
  5. Gregoriadis G. Overview of liposomes. J Antimicrob Chemother. 1991 Oct;28 (Suppl B):39–48. doi: 10.1093/jac/28.suppl_b.39. [DOI] [PubMed] [Google Scholar]
  6. Harashima H., Ohnishi Y., Kiwada H. In vivo evaluation of the effect of the size and opsonization on the hepatic extraction of liposomes in rats: an application of Oldendorf method. Biopharm Drug Dispos. 1992 Oct;13(7):549–553. doi: 10.1002/bdd.2510130708. [DOI] [PubMed] [Google Scholar]
  7. Harashima H., Sakata K., Kiwada H. Distinction between the depletion of opsonins and the saturation of uptake in the dose-dependent hepatic uptake of liposomes. Pharm Res. 1993 Apr;10(4):606–610. doi: 10.1023/a:1018918623658. [DOI] [PubMed] [Google Scholar]
  8. Harashima H., Yamane C., Kume Y., Kiwada H. Kinetic analysis of AUC-dependent saturable clearance of liposomes: mathematical description of AUC dependency. J Pharmacokinet Biopharm. 1993 Jun;21(3):299–308. doi: 10.1007/BF01059781. [DOI] [PubMed] [Google Scholar]
  9. Hostetler J. S., Clemons K. V., Hanson L. H., Stevens D. A. Efficacy and safety of amphotericin B colloidal dispersion compared with those of amphotericin B deoxycholate suspension for treatment of disseminated murine cryptococcosis. Antimicrob Agents Chemother. 1992 Dec;36(12):2656–2660. doi: 10.1128/aac.36.12.2656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Huang S. K., Lee K. D., Hong K., Friend D. S., Papahadjopoulos D. Microscopic localization of sterically stabilized liposomes in colon carcinoma-bearing mice. Cancer Res. 1992 Oct 1;52(19):5135–5143. [PubMed] [Google Scholar]
  11. Janknegt R., de Marie S., Bakker-Woudenberg I. A., Crommelin D. J. Liposomal and lipid formulations of amphotericin B. Clinical pharmacokinetics. Clin Pharmacokinet. 1992 Oct;23(4):279–291. doi: 10.2165/00003088-199223040-00004. [DOI] [PubMed] [Google Scholar]
  12. Joly V., Dromer F., Barge J., Yeni P., Seta N., Molas G., Carbon C. Incorporation of amphotericin B (AMB) into liposomes alters AMB-induced acute nephrotoxicity in rabbits. J Pharmacol Exp Ther. 1989 Oct;251(1):311–316. [PubMed] [Google Scholar]
  13. Kume Y., Maeda F., Harashima H., Kiwada H. Saturable, non-Michaelis-Menten uptake of liposomes by the reticuloendothelial system. J Pharm Pharmacol. 1991 Mar;43(3):162–166. doi: 10.1111/j.2042-7158.1991.tb06658.x. [DOI] [PubMed] [Google Scholar]
  14. Litzinger D. C., Buiting A. M., van Rooijen N., Huang L. Effect of liposome size on the circulation time and intraorgan distribution of amphipathic poly(ethylene glycol)-containing liposomes. Biochim Biophys Acta. 1994 Feb 23;1190(1):99–107. doi: 10.1016/0005-2736(94)90038-8. [DOI] [PubMed] [Google Scholar]
  15. Litzinger D. C., Huang L. Amphipathic poly(ethylene glycol) 5000-stabilized dioleoylphosphatidylethanolamine liposomes accumulate in spleen. Biochim Biophys Acta. 1992 Aug 19;1127(3):249–254. doi: 10.1016/0005-2760(92)90228-n. [DOI] [PubMed] [Google Scholar]
  16. Liu D., Liu F., Song Y. K. Recognition and clearance of liposomes containing phosphatidylserine are mediated by serum opsonin. Biochim Biophys Acta. 1995 Apr 12;1235(1):140–146. doi: 10.1016/0005-2736(95)00005-n. [DOI] [PubMed] [Google Scholar]
  17. Liu D., Mori A., Huang L. Large liposomes containing ganglioside GM1 accumulate effectively in spleen. Biochim Biophys Acta. 1991 Jul 22;1066(2):159–165. doi: 10.1016/0005-2736(91)90182-8. [DOI] [PubMed] [Google Scholar]
  18. Lopez-Berestein G., Bodey G. P., Fainstein V., Keating M., Frankel L. S., Zeluff B., Gentry L., Mehta K. Treatment of systemic fungal infections with liposomal amphotericin B. Arch Intern Med. 1989 Nov;149(11):2533–2536. [PubMed] [Google Scholar]
  19. Lopez-Berestein G., Bodey G. P., Frankel L. S., Mehta K. Treatment of hepatosplenic candidiasis with liposomal-amphotericin B. J Clin Oncol. 1987 Feb;5(2):310–317. doi: 10.1200/JCO.1987.5.2.310. [DOI] [PubMed] [Google Scholar]
  20. Lopez-Berestein G., Fainstein V., Hopfer R., Mehta K., Sullivan M. P., Keating M., Rosenblum M. G., Mehta R., Luna M., Hersh E. M. Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: a preliminary study. J Infect Dis. 1985 Apr;151(4):704–710. doi: 10.1093/infdis/151.4.704. [DOI] [PubMed] [Google Scholar]
  21. Medoff G., Valeriote F., Dieckman J. Potentiation of anticancer agents by amphotericin B. J Natl Cancer Inst. 1981 Jul;67(1):131–135. [PubMed] [Google Scholar]
  22. Meunier F., Prentice H. G., Ringdén O. Liposomal amphotericin B (AmBisome): safety data from a phase II/III clinical trial. J Antimicrob Chemother. 1991 Oct;28 (Suppl B):83–91. doi: 10.1093/jac/28.suppl_b.83. [DOI] [PubMed] [Google Scholar]
  23. Meunier F., Sculier J. P., Coune A., Brassinne C., Heyman C., Laduron C., Collette N., Hollaert C., Bron D., Klastersky J. Amphotericin B encapsulated in liposomes administered to cancer patients. Ann N Y Acad Sci. 1988;544:598–610. doi: 10.1111/j.1749-6632.1988.tb40460.x. [DOI] [PubMed] [Google Scholar]
  24. Olsen S. J., Swerdel M. R., Blue B., Clark J. M., Bonner D. P. Tissue distribution of amphotericin B lipid complex in laboratory animals. J Pharm Pharmacol. 1991 Dec;43(12):831–835. doi: 10.1111/j.2042-7158.1991.tb03189.x. [DOI] [PubMed] [Google Scholar]
  25. Osaka S., Tsuji H., Kiwada H. Uptake of liposomes surface-modified with glycyrrhizin by primary cultured rat hepatocytes. Biol Pharm Bull. 1994 Jul;17(7):940–943. doi: 10.1248/bpb.17.940. [DOI] [PubMed] [Google Scholar]
  26. Ralph E. D., Khazindar A. M., Barber K. R., Grant C. W. Comparative in vitro effects of liposomal amphotericin B, amphotericin B-deoxycholate, and free amphotericin B against fungal strains determined by using MIC and minimal lethal concentration susceptibility studies and time-kill curves. Antimicrob Agents Chemother. 1991 Jan;35(1):188–191. doi: 10.1128/aac.35.1.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ringdén O., Meunier F., Tollemar J., Ricci P., Tura S., Kuse E., Viviani M. A., Gorin N. C., Klastersky J., Fenaux P. Efficacy of amphotericin B encapsulated in liposomes (AmBisome) in the treatment of invasive fungal infections in immunocompromised patients. J Antimicrob Chemother. 1991 Oct;28 (Suppl B):73–82. doi: 10.1093/jac/28.suppl_b.73. [DOI] [PubMed] [Google Scholar]
  28. Sabra R., Branch R. A. Amphotericin B nephrotoxicity. Drug Saf. 1990 Mar-Apr;5(2):94–108. doi: 10.2165/00002018-199005020-00003. [DOI] [PubMed] [Google Scholar]
  29. Taylor R. L., Williams D. M., Craven P. C., Graybill J. R., Drutz D. J., Magee W. E. Amphotericin B in liposomes: a novel therapy for histoplasmosis. Am Rev Respir Dis. 1982 May;125(5):610–611. doi: 10.1164/arrd.1982.125.5.610. [DOI] [PubMed] [Google Scholar]
  30. Torchilin V. P., Shtilman M. I., Trubetskoy V. S., Whiteman K., Milstein A. M. Amphiphilic vinyl polymers effectively prolong liposome circulation time in vivo. Biochim Biophys Acta. 1994 Oct 12;1195(1):181–184. doi: 10.1016/0005-2736(94)90025-6. [DOI] [PubMed] [Google Scholar]
  31. Wiebe V. J., DeGregorio M. W. Liposome-encapsulated amphotericin B: a promising new treatment for disseminated fungal infections. Rev Infect Dis. 1988 Nov-Dec;10(6):1097–1101. doi: 10.1093/clinids/10.6.1097. [DOI] [PubMed] [Google Scholar]
  32. Yamauchi H., Kikuchi H., Sawada M., Tomikawa M., Hirota S. Characterization and tissue distribution of liposomes containing lactose mono-fatty acid derivatives. J Microencapsul. 1994 Mar-Apr;11(2):179–188. doi: 10.3109/02652049409040449. [DOI] [PubMed] [Google Scholar]
  33. Yamauchi H., Kikuchi H., Sawada M., Tomikawa M., Hirota S. Selective uptake of liposomes containing lactose mono-fatty acid derivatives by hepatic parenchymal cells. J Microencapsul. 1994 May-Jun;11(3):287–296. doi: 10.3109/02652049409040458. [DOI] [PubMed] [Google Scholar]
  34. Yoshioka S., Imaeda N., Okano Y., Mizukami Y., Katagiri Y. Preferential uptake of lactosylceramide-bearing dipalmitoylphosphatidylcholine-liposomes into liver: role of membrane fluidity. Biol Pharm Bull. 1994 May;17(5):640–644. doi: 10.1248/bpb.17.640. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES