Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1993 Mar;37(3):512–522. doi: 10.1128/aac.37.3.512

Pharmacokinetics and pharmacodynamics of granulocyte-macrophage colony-stimulating factor and zidovudine in patients with AIDS and severe AIDS-related complex.

R G Hewitt 1, G D Morse 1, W D Lawrence 1, M L Maliszewski 1, J Santora 1, L Bartos 1, E Bonnem 1, B Poiesz 1
PMCID: PMC187701  PMID: 8460920

Abstract

Granulocytopenia is a complication of human immunodeficiency virus disease, as well as a toxic manifestation of zidovudine therapy. To evaluate pharmacokinetic and pharmacodynamic relationships, 11 AIDS-AIDS-related complex patients who had developed zidovudine-associated granulocytopenia (mean absolute neutrophil count, 1,077/mm3) were examined after addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to zidovudine. GM-CSF was administered as a daily (1.0 or 0.3 micrograms/kg) or every-other-day (0.3 micrograms/kg) subcutaneous dose over a 28-day period. Zidovudine was continued at the same daily dosage as was previously being administered. Of 11 patients, 7 (1.0 micrograms/kg, n = 5; 0.3 micrograms/kg, n = 2) had a pharmacologic response to GM-CSF with an increase to a mean absolute neutrophil count of 3,189 cells per mm3 at 4 weeks (P < 0.05). The peak concentration of GM-CSF in plasma ranged from 11.5 to 84.4 pg/ml, and the time to peak ranged from 1 to 3 h. No correlation between GM-CSF disposition and hematologic response was noted. A decreased plasma zidovudine-glucuronide/zidovudine ratio was noted after 1 week of GM-CSF, and an increase in the area under the plasma concentration-versus-time curve for zidovudine was found in three patients after 4 weeks. Low doses of GM-CSF can raise the granulocyte count in patients with zidovudine-induced neutropenia. The use of GM-CSF and zidovudine may represent a viable treatment option for persons with human immunodeficiency virus infection who develop neutropenia while receiving zidovudine but do not tolerate alternative nucleoside analogs. Further studies are needed to assess the complex interaction between these two agents.

Full text

PDF
512

Selected References

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

  1. Abrams D. I., Chinn E. K., Lewis B. J., Volberding P. A., Conant M. A., Townsend R. M. Hematologic manifestations in homosexual men with Kaposi's sarcoma. Am J Clin Pathol. 1984 Jan;81(1):13–18. doi: 10.1093/ajcp/81.1.13. [DOI] [PubMed] [Google Scholar]
  2. Baldwin G. C., Gasson J. C., Quan S. G., Fleischmann J., Weisbart R., Oette D., Mitsuyasu R. T., Golde D. W. Granulocyte-macrophage colony-stimulating factor enhances neutrophil function in acquired immunodeficiency syndrome patients. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2763–2766. doi: 10.1073/pnas.85.8.2763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cebon J., Dempsey P., Fox R., Kannourakis G., Bonnem E., Burgess A. W., Morstyn G. Pharmacokinetics of human granulocyte-macrophage colony-stimulating factor using a sensitive immunoassay. Blood. 1988 Oct;72(4):1340–1347. [PubMed] [Google Scholar]
  4. Clark S. C., Kamen R. The human hematopoietic colony-stimulating factors. Science. 1987 Jun 5;236(4806):1229–1237. doi: 10.1126/science.3296190. [DOI] [PubMed] [Google Scholar]
  5. Davatelis G., Wolpe S. D., Sherry B., Dayer J. M., Chicheportiche R., Cerami A. Macrophage inflammatory protein-1: a prostaglandin-independent endogenous pyrogen. Science. 1989 Feb 24;243(4894 Pt 1):1066–1068. doi: 10.1126/science.2646711. [DOI] [PubMed] [Google Scholar]
  6. Davey R. T., Jr, Davey V. J., Metcalf J. A., Zurlo J. J., Kovacs J. A., Falloon J., Polis M. A., Zunich K. M., Masur H., Lane H. C. A phase I/II trial of zidovudine, interferon-alpha, and granulocyte-macrophage colony-stimulating factor in the treatment of human immunodeficiency virus type 1 infection. J Infect Dis. 1991 Jul;164(1):43–52. doi: 10.1093/infdis/164.1.43. [DOI] [PubMed] [Google Scholar]
  7. Ellis M., Gupta S., Galant S., Hakim S., VandeVen C., Toy C., Cairo M. S. Impaired neutrophil function in patients with AIDS or AIDS-related complex: a comprehensive evaluation. J Infect Dis. 1988 Dec;158(6):1268–1276. doi: 10.1093/infdis/158.6.1268. [DOI] [PubMed] [Google Scholar]
  8. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  9. Fischl M., Galpin J. E., Levine J. D., Groopman J. E., Henry D. H., Kennedy P., Miles S., Robbins W., Starrett B., Zalusky R. Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med. 1990 May 24;322(21):1488–1493. doi: 10.1056/NEJM199005243222103. [DOI] [PubMed] [Google Scholar]
  10. Folks T. M., Justement J., Kinter A., Dinarello C. A., Fauci A. S. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987 Nov 6;238(4828):800–802. doi: 10.1126/science.3313729. [DOI] [PubMed] [Google Scholar]
  11. Good S. S., Reynolds D. J., de Miranda P. Simultaneous quantification of zidovudine and its glucuronide in serum by high-performance liquid chromatography. J Chromatogr. 1988 Sep 23;431(1):123–133. doi: 10.1016/s0378-4347(00)83075-3. [DOI] [PubMed] [Google Scholar]
  12. Groopman J. E., Mitsuyasu R. T., DeLeo M. J., Oette D. H., Golde D. W. Effect of recombinant human granulocyte-macrophage colony-stimulating factor on myelopoiesis in the acquired immunodeficiency syndrome. N Engl J Med. 1987 Sep 3;317(10):593–598. doi: 10.1056/NEJM198709033171003. [DOI] [PubMed] [Google Scholar]
  13. Groopman J. E., Molina J. M., Scadden D. T. Hematopoietic growth factors. Biology and clinical applications. N Engl J Med. 1989 Nov 23;321(21):1449–1459. doi: 10.1056/NEJM198911233212106. [DOI] [PubMed] [Google Scholar]
  14. Hammer S. M., Gillis J. M. Synergistic activity of granulocyte-macrophage colony-stimulating factor and 3'-azido-3'-deoxythymidine against human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 1987 Jul;31(7):1046–1050. doi: 10.1128/aac.31.7.1046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klecker R. W., Jr, Collins J. M., Yarchoan R., Thomas R., Jenkins J. F., Broder S., Myers C. E. Plasma and cerebrospinal fluid pharmacokinetics of 3'-azido-3'-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther. 1987 Apr;41(4):407–412. doi: 10.1038/clpt.1987.49. [DOI] [PubMed] [Google Scholar]
  16. Koenig S., Gendelman H. E., Orenstein J. M., Dal Canto M. C., Pezeshkpour G. H., Yungbluth M., Janotta F., Aksamit A., Martin M. A., Fauci A. S. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science. 1986 Sep 5;233(4768):1089–1093. doi: 10.1126/science.3016903. [DOI] [PubMed] [Google Scholar]
  17. Murphy P. M., Lane H. C., Fauci A. S., Gallin J. I. Impairment of neutrophil bactericidal capacity in patients with AIDS. J Infect Dis. 1988 Sep;158(3):627–630. doi: 10.1093/infdis/158.3.627. [DOI] [PubMed] [Google Scholar]
  18. Nielsen H., Kharazmi A., Faber V. Blood monocyte and neutrophil functions in the acquired immune deficiency syndrome. Scand J Immunol. 1986 Sep;24(3):291–296. doi: 10.1111/j.1365-3083.1986.tb02096.x. [DOI] [PubMed] [Google Scholar]
  19. Perno C. F., Yarchoan R., Cooney D. A., Hartman N. R., Webb D. S., Hao Z., Mitsuya H., Johns D. G., Broder S. Replication of human immunodeficiency virus in monocytes. Granulocyte/macrophage colony-stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2'3'-dideoxythymidine (AZT) and other dideoxynucleoside congeners of thymidine. J Exp Med. 1989 Mar 1;169(3):933–951. doi: 10.1084/jem.169.3.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pluda J. M., Yarchoan R., Smith P. D., McAtee N., Shay L. E., Oette D., Maha M., Wahl S. M., Myers C. E., Broder S. Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection. Blood. 1990 Aug 1;76(3):463–472. [PubMed] [Google Scholar]
  21. Portegies P., de Gans J., Lange J. M., Derix M. M., Speelman H., Bakker M., Danner S. A., Goudsmit J. Declining incidence of AIDS dementia complex after introduction of zidovudine treatment. BMJ. 1989 Sep 30;299(6703):819–821. doi: 10.1136/bmj.299.6703.819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Richman D. D., Fischl M. A., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Hirsch M. S. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):192–197. doi: 10.1056/NEJM198707233170402. [DOI] [PubMed] [Google Scholar]
  23. Roberts D. E., Berman S. M., Nakasato S., Wyle F. A., Wishnow R. M., Segal G. P. Effect of lithium carbonate on zidovudine-associated neutropenia in the acquired immunodeficiency syndrome. Am J Med. 1988 Sep;85(3):428–431. doi: 10.1016/0002-9343(88)90601-8. [DOI] [PubMed] [Google Scholar]
  24. Rocci M. L., Jr, Jusko W. J. LAGRAN program for area and moments in pharmacokinetic analysis. Comput Programs Biomed. 1983 Jun;16(3):203–216. doi: 10.1016/0010-468x(83)90082-x. [DOI] [PubMed] [Google Scholar]
  25. Ruef C., Coleman D. L. Granulocyte-macrophage colony-stimulating factor: pleiotropic cytokine with potential clinical usefulness. Rev Infect Dis. 1990 Jan-Feb;12(1):41–62. doi: 10.1093/clinids/12.1.41. [DOI] [PubMed] [Google Scholar]
  26. Shaunak S., Bartlett J. A. Zidovudine-induced neutropenia: are we too cautious? Lancet. 1989 Jul 8;2(8654):91–92. doi: 10.1016/s0140-6736(89)90325-5. [DOI] [PubMed] [Google Scholar]
  27. Sieff C. A. Hematopoietic growth factors. J Clin Invest. 1987 Jun;79(6):1549–1557. doi: 10.1172/JCI112988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sisson S. D., Dinarello C. A. Production of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor by human mononuclear cells stimulated with granulocyte-macrophage colony-stimulating factor. Blood. 1988 Oct;72(4):1368–1374. [PubMed] [Google Scholar]
  29. Spivak J. L., Bender B. S., Quinn T. C. Hematologic abnormalities in the acquired immune deficiency syndrome. Am J Med. 1984 Aug;77(2):224–228. doi: 10.1016/0002-9343(84)90695-8. [DOI] [PubMed] [Google Scholar]
  30. Volberding P. A., Lagakos S. W., Koch M. A., Pettinelli C., Myers M. W., Booth D. K., Balfour H. H., Jr, Reichman R. C., Bartlett J. A., Hirsch M. S. Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. N Engl J Med. 1990 Apr 5;322(14):941–949. doi: 10.1056/NEJM199004053221401. [DOI] [PubMed] [Google Scholar]
  31. Weisbart R. H., Gasson J. C., Golde D. W. Colony-stimulating factors and host defense. Ann Intern Med. 1989 Feb 15;110(4):297–303. doi: 10.7326/0003-4819-110-4-297. [DOI] [PubMed] [Google Scholar]
  32. Zon L. I., Arkin C., Groopman J. E. Haematologic manifestations of the human immune deficiency virus (HIV). Br J Haematol. 1987 Jun;66(2):251–256. doi: 10.1111/j.1365-2141.1987.tb01307.x. [DOI] [PubMed] [Google Scholar]

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

RESOURCES