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. 1995 Sep;39(9):1973–1978. doi: 10.1128/aac.39.9.1973

Liposomal encapsulation of foscarnet protects against hypocalcemia induced by free foscarnet.

R F Omar 1, N Dusserre 1, A Désormeaux 1, L Poulin 1, M Tremblay 1, D Beauchamp 1, M G Bergeron 1
PMCID: PMC162866  PMID: 8540701

Abstract

Hypocalcemia and an increase in creatinine level are the most important serious effects associated with foscarnet (PFA) therapy. In an animal model, we have explored the potential protective role of liposome-encapsulated foscarnet (LE-PFA) on these metabolic abnormalities. PFA administered as one bolus injection (0.5 or 1.0 g/kg) caused significant rapid decreases (approximately 20%) in the levels of calcium and phosphorus in serum within a few minutes and up to 30 min after injection. LE-PFA did not induce any of these changes, while peak levels in serum and the half-life of this formulation were much higher than those of the free drug. PFA administered for 2 weeks (340 or 500 mg/kg/day) resulted in no changes in creatinine or blood urea nitrogen levels in serum at the low-dosage level, but at the higher-dosage level, the creatinine level in serum increased by day 5 posttreatment. Furthermore, there was no increase in the creatinine or blood urea nitrogen level after 2 weeks of treatment with LE-PFA at a dosage of 35 mg/kg/day. When the pharmacokinetics of both free PFA and LE-PFA were compared, the plasma half-life of the encapsulated drug was approximately four times longer than that of the free drug. In addition, the systemic clearance of LE-PFA was approximately one-fifth of that of the free drug. In conclusion, free PFA causes hypocalcemia and hypophosphatemia and increases the creatinine level in serum, whereas the LE form of this drug seems to protect against the abnormal changes in calcium and phosphorus levels caused by the free drug. By preventing hypocalcemia and increasing its half-life, LE-PFA can be used at lower doses and at longer intervals. Clinical investigations of these formulations may be worthwhile.

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Selected References

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  1. Allen T. M., Hansen C. B., Guo L. S. Subcutaneous administration of liposomes: a comparison with the intravenous and intraperitoneal routes of injection. Biochim Biophys Acta. 1993 Jul 25;1150(1):9–16. doi: 10.1016/0005-2736(93)90115-g. [DOI] [PubMed] [Google Scholar]
  2. Bakker-Woudenberg I. A., Lokerse A. F., ten Kate M. Increased efficacy of ganciclovir and foscarnet inhibition of cytomegalovirus replication in vitro by encapsulation in liposomes. Scand J Infect Dis Suppl. 1990;74:54–57. [PubMed] [Google Scholar]
  3. Cacoub P., Deray G., Baumelou A., Le Hoang P., Rozenbaum W., Gentilini M., Soubrie C., Rousselie R., Jacobs C. Acute renal failure induced by foscarnet: 4 cases. Clin Nephrol. 1988 Jun;29(6):315–318. [PubMed] [Google Scholar]
  4. Chrisp P., Clissold S. P. Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. Drugs. 1991 Jan;41(1):104–129. doi: 10.2165/00003495-199141010-00009. [DOI] [PubMed] [Google Scholar]
  5. Deray G., Martinez F., Katlama C., Levaltier B., Beaufils H., Danis M., Rozenheim M., Baumelou A., Dohin E., Gentilini M. Foscarnet nephrotoxicity: mechanism, incidence and prevention. Am J Nephrol. 1989;9(4):316–321. doi: 10.1159/000167987. [DOI] [PubMed] [Google Scholar]
  6. Désormeaux A., Harvie P., Perron S., Makabi-Panzu B., Beauchamp D., Tremblay M., Poulin L., Bergeron M. G. Antiviral efficacy, intracellular uptake and pharmacokinetics of free and liposome-encapsulated 2',3'-dideoxyinosine. AIDS. 1994 Nov;8(11):1545–1553. doi: 10.1097/00002030-199411000-00005. [DOI] [PubMed] [Google Scholar]
  7. Eriksson B. F., Schinazi R. F. Combinations of 3'-azido-3'-deoxythymidine (zidovudine) and phosphonoformate (foscarnet) against human immunodeficiency virus type 1 and cytomegalovirus replication in vitro. Antimicrob Agents Chemother. 1989 May;33(5):663–669. doi: 10.1128/aac.33.5.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fanning M. M., Read S. E., Benson M., Vas S., Rachlis A., Kozousek V., Mortimer C., Harvey P., Schwartz C., Chew E. Foscarnet therapy of cytomegalovirus retinitis in AIDS. J Acquir Immune Defic Syndr. 1990;3(5):472–479. [PubMed] [Google Scholar]
  9. Farthing C., Anderson M. G., Ellis M. E., Gazzard B. G., Chanas A. C. Treatment of cytomegalovirus pneumonitis with foscarnet (trisodium phosphonoformate) in patients with AIDS. J Med Virol. 1987 Jun;22(2):157–162. doi: 10.1002/jmv.1890220206. [DOI] [PubMed] [Google Scholar]
  10. Fletcher C. V., Collier A. C., Rhame F. S., Bennett D., Para M. F., Beatty C. C., Jones C. E., Balfour H. H., Jr Foscarnet for suppression of human immunodeficiency virus replication. Antimicrob Agents Chemother. 1994 Mar;38(3):604–607. doi: 10.1128/aac.38.3.604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jacobson M. A., Crowe S., Levy J., Aweeka F., Gambertoglio J., McManus N., Mills J. Effect of Foscarnet therapy on infection with human immunodeficiency virus in patients with AIDS. J Infect Dis. 1988 Oct;158(4):862–865. [PubMed] [Google Scholar]
  12. Jacobson M. A., O'Donnell J. J., Mills J. Foscarnet treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Antimicrob Agents Chemother. 1989 May;33(5):736–741. doi: 10.1128/aac.33.5.736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jacobson M. A. Review of the toxicities of foscarnet. J Acquir Immune Defic Syndr. 1992;5 (Suppl 1):S11–S17. [PubMed] [Google Scholar]
  14. Karlowsky J. A., Zhanel G. G. Concepts on the use of liposomal antimicrobial agents: applications for aminoglycosides. Clin Infect Dis. 1992 Oct;15(4):654–667. doi: 10.1093/clind/15.4.654. [DOI] [PubMed] [Google Scholar]
  15. Makabi-Panzu B., Lessard C., Beauchamp D., Désormeaux A., Poulin L., Tremblay M., Bergeron M. G. Uptake and binding of liposomal 2',3'-dideoxycytidine by RAW 264.7 cells: a three-step process. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Mar 1;8(3):227–235. doi: 10.1097/00042560-199503010-00002. [DOI] [PubMed] [Google Scholar]
  16. Nicotera P., McConkey D. J., Dypbukt J. M., Jones D. P., Orrenius S. Ca2+-activated mechanisms in cell killing. Drug Metab Rev. 1989;20(2-4):193–201. doi: 10.3109/03602538909103536. [DOI] [PubMed] [Google Scholar]
  17. Oberg B. Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacol Ther. 1989;40(2):213–285. doi: 10.1016/0163-7258(89)90097-1. [DOI] [PubMed] [Google Scholar]
  18. Orrenius S., McConkey D. J., Bellomo G., Nicotera P. Role of Ca2+ in toxic cell killing. Trends Pharmacol Sci. 1989 Jul;10(7):281–285. doi: 10.1016/0165-6147(89)90029-1. [DOI] [PubMed] [Google Scholar]
  19. Palestine A. G., Polis M. A., De Smet M. D., Baird B. F., Falloon J., Kovacs J. A., Davey R. T., Zurlo J. J., Zunich K. M., Davis M. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med. 1991 Nov 1;115(9):665–673. doi: 10.7326/0003-4819-115-9-665. [DOI] [PubMed] [Google Scholar]
  20. Perez-Soler R. Liposomes as carriers of antitumor agents: toward a clinical reality. Cancer Treat Rev. 1989 Jun;16(2):67–82. doi: 10.1016/0305-7372(89)90011-x. [DOI] [PubMed] [Google Scholar]
  21. Phillips N. C., Skamene E., Tsoukas C. Liposomal encapsulation of 3'-azido-3'-deoxythymidine (AZT) results in decreased bone marrow toxicity and enhanced activity against murine AIDS-induced immunosuppression. J Acquir Immune Defic Syndr. 1991;4(10):959–966. [PubMed] [Google Scholar]
  22. Phillips N. C., Tsoukas C. Liposomal encapsulation of azidothymidine results in decreased hematopoietic toxicity and enhanced activity against murine acquired immunodeficiency syndrome. Blood. 1992 Mar 1;79(5):1137–1143. [PubMed] [Google Scholar]
  23. Pidgeon C., McNeely S., Schmidt T., Johnson J. E. Multilayered vesicles prepared by reverse-phase evaporation: liposome structure and optimum solute entrapment. Biochemistry. 1987 Jan 13;26(1):17–29. doi: 10.1021/bi00375a004. [DOI] [PubMed] [Google Scholar]
  24. Proffitt R. T., Satorius A., Chiang S. M., Sullivan L., Adler-Moore J. P. Pharmacology and toxicology of a liposomal formulation of amphotericin B (AmBisome) in rodents. J Antimicrob Chemother. 1991 Oct;28 (Suppl B):49–61. doi: 10.1093/jac/28.suppl_b.49. [DOI] [PubMed] [Google Scholar]
  25. Ringdén O., Lönnqvist B., Paulin T., Ahlmén J., Klintmalm G., Wahren B., Lernestedt J. O. Pharmacokinetics, safety and preliminary clinical experiences using foscarnet in the treatment of cytomegalovirus infections in bone marrow and renal transplant recipients. J Antimicrob Chemother. 1986 Mar;17(3):373–387. doi: 10.1093/jac/17.3.373. [DOI] [PubMed] [Google Scholar]
  26. Sandstrom E. G., Kaplan J. C., Byington R. E., Hirsch M. S. Inhibition of human T-cell lymphotropic virus type III in vitro by phosphonoformate. Lancet. 1985 Jun 29;1(8444):1480–1482. doi: 10.1016/s0140-6736(85)92255-x. [DOI] [PubMed] [Google Scholar]
  27. Szoka F. C., Jr, Chu C. J. Increased efficacy of phosphonoformate and phosphonoacetate inhibition of herpes simplex virus type 2 replication by encapsulation in liposomes. Antimicrob Agents Chemother. 1988 Jun;32(6):858–864. doi: 10.1128/aac.32.6.858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Szoka F., Olson F., Heath T., Vail W., Mayhew E., Papahadjopoulos D. Preparation of unilamellar liposomes of intermediate size (0.1-0.2 mumol) by a combination of reverse phase evaporation and extrusion through polycarbonate membranes. Biochim Biophys Acta. 1980 Oct 2;601(3):559–571. doi: 10.1016/0005-2736(80)90558-1. [DOI] [PubMed] [Google Scholar]
  29. Walmsley S. L., Chew E., Read S. E., Vellend H., Salit I., Rachlis A., Fanning M. M. Treatment of cytomegalovirus retinitis with trisodium phosphonoformate hexahydrate (Foscarnet). J Infect Dis. 1988 Mar;157(3):569–572. doi: 10.1093/infdis/157.3.569. [DOI] [PubMed] [Google Scholar]
  30. Youle M. S., Clarbour J., Gazzard B., Chanas A. Severe hypocalcaemia in AIDS patients treated with foscarnet and pentamidine. Lancet. 1988 Jun 25;1(8600):1455–1456. doi: 10.1016/s0140-6736(88)92260-x. [DOI] [PubMed] [Google Scholar]

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