Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1996 Jan;40(1):161–165. doi: 10.1128/aac.40.1.161

Effects of cytokines on antiviral pharmacokinetics: an alternative approach to assessment of drug interactions using bioequivalence guidelines.

S C Piscitelli 1, M A Amatea 1, S Vogel 1, C Bechtel 1, J A Metcalf 1, J A Kovacs 1
PMCID: PMC163076  PMID: 8787899

Abstract

The effects of cytokines on the pharmacokinetics of nucleoside analogs were evaluated in two separate studies using zidovudine in combination with interleukin-2 and didanosine in combination with alpha interferon. In each study, drug interactions were evaluated by using both a standard method (Student's t test) and bioequivalence testing. Serial blood samples were collected from human immunodeficiency virus-infected patients prior to and during cytokine therapy for determination of nucleoside analog concentrations. Concentrations were fit separately to a two-compartment model by using the iterative two-stage approach to population analysis. No alterations in area under the curve or oral clearance were observed for either drug during combination therapy. In general, there was good agreement between statistical methods for determining if antiviral pharmacokinetic parameters were altered by concomitant cytokine therapy. However, large individual changes in the maximum concentration of zidovudine in serum were detected by bioequivalence testing but no difference was found by Student's t test. For didanosine, significant but clinically irrelevant decreases determined by standard hypothesis testing were seen for both the volume of the central compartment (1.91 to 1.86 liters) and the absorption rate constant (0.79 to 0.73 h-1) in the presence of alpha interferon. No interaction was noted for these parameters by using bioequivalence guidelines. Bioequivalence testing may provide an alternative approach to assessment of drug interactions. Interleukin-2 and alpha interferon do not alter the pharmacokinetics of zidovudine and didanosine, respectively.

Full Text

The Full Text of this article is available as a PDF (189.4 KB).

Selected References

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

  1. Chen Y. L., Le Vraux V., Leneveu A., Dreyfus F., Stheneur A., Florentin I., De Sousa M., Giroud J. P., Flouvat B., Chauvelot-Moachon L. Acute-phase response, interleukin-6, and alteration of cyclosporine pharmacokinetics. Clin Pharmacol Ther. 1994 Jun;55(6):649–660. doi: 10.1038/clpt.1994.82. [DOI] [PubMed] [Google Scholar]
  2. Cordaro J. A., Morse G. D., Bartos L., Gugino L. J., Maliszewski M., Colomaio R., Shelton M., O'Donnell A., Hewitt R. Zidovudine pharmacokinetics in HIV-positive women during different phases of the menstrual cycle. Pharmacotherapy. 1993 Jul-Aug;13(4):369–377. [PubMed] [Google Scholar]
  3. 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]
  4. Frissen P. H., van der Ende M. E., ten Napel C. H., Weigel H. M., Schreij G. S., Kauffmann R. H., Koopmans P. P., Hoepelman A. I., de Boer J. B., Weverling G. J. Zidovudine and interferon-alpha combination therapy versus zidovudine monotherapy in subjects with symptomatic human immunodeficiency virus type 1 infection. J Infect Dis. 1994 Jun;169(6):1351–1355. doi: 10.1093/infdis/169.6.1351. [DOI] [PubMed] [Google Scholar]
  5. Hartshorn K. L., Vogt M. W., Chou T. C., Blumberg R. S., Byington R., Schooley R. T., Hirsch M. S. Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon. Antimicrob Agents Chemother. 1987 Feb;31(2):168–172. doi: 10.1128/aac.31.2.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kassler W. J., Blanc P., Greenblatt R. The use of medicinal herbs by human immunodeficiency virus-infected patients. Arch Intern Med. 1991 Nov;151(11):2281–2288. [PubMed] [Google Scholar]
  7. Knupp C. A., Stancato F. A., Papp E. A., Barbhaiya R. H. Quantitation of didanosine in human plasma and urine by high-performance liquid chromatography. J Chromatogr. 1990 Nov 30;533:282–290. doi: 10.1016/s0378-4347(00)82215-x. [DOI] [PubMed] [Google Scholar]
  8. Kovacs J. A., Baseler M., Dewar R. J., Vogel S., Davey R. T., Jr, Falloon J., Polis M. A., Walker R. E., Stevens R., Salzman N. P. Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. A preliminary study. N Engl J Med. 1995 Mar 2;332(9):567–575. doi: 10.1056/NEJM199503023320904. [DOI] [PubMed] [Google Scholar]
  9. Kovacs J. A., Deyton L., Davey R., Falloon J., Zunich K., Lee D., Metcalf J. A., Bigley J. W., Sawyer L. A., Zoon K. C. Combined zidovudine and interferon-alpha therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS) Ann Intern Med. 1989 Aug 15;111(4):280–287. doi: 10.7326/0003-4819-111-4-280. [DOI] [PubMed] [Google Scholar]
  10. Lane H. C., Davey V., Kovacs J. A., Feinberg J., Metcalf J. A., Herpin B., Walker R., Deyton L., Davey R. T., Jr, Falloon J. Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial. Ann Intern Med. 1990 Jun 1;112(11):805–811. doi: 10.7326/0003-4819-112-11-805. [DOI] [PubMed] [Google Scholar]
  11. Morse G. D., Portmore A., Olson J., Taylor C., Plank C., Reichman R. C. Multiple-dose pharmacokinetics of oral zidovudine in hemophilia patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1990 Mar;34(3):394–397. doi: 10.1128/aac.34.3.394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Pai S. M., Shukla U. A., Grasela T. H., Knupp C. A., Dolin R., Valentine F. T., McLaren C., Liebman H. A., Martin R. R., Pittman K. A. Population pharmacokinetic analysis of didanosine (2',3'-dideoxyinosine) plasma concentrations obtained in phase I clinical trials in patients with AIDS or AIDS-related complex. J Clin Pharmacol. 1992 Mar;32(3):242–247. doi: 10.1002/j.1552-4604.1992.tb03832.x. [DOI] [PubMed] [Google Scholar]
  13. Rook A. H., Masur H., Lane H. C., Frederick W., Kasahara T., Macher A. M., Djeu J. Y., Manischewitz J. F., Jackson L., Fauci A. S. Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome. J Clin Invest. 1983 Jul;72(1):398–403. doi: 10.1172/JCI110981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Schuirmann D. J. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987 Dec;15(6):657–680. doi: 10.1007/BF01068419. [DOI] [PubMed] [Google Scholar]
  15. Schwartz D. H., Merigan T. C. Interleukin-2 in the treatment of HIV disease. Biotherapy. 1990;2(2):119–136. doi: 10.1007/BF02173452. [DOI] [PubMed] [Google Scholar]
  16. Sneller M. C., Lane H. C. Immunologic approaches to the therapy of HIV-1 infection. Ann N Y Acad Sci. 1993 Jun 23;685:687–696. doi: 10.1111/j.1749-6632.1993.tb35932.x. [DOI] [PubMed] [Google Scholar]
  17. Steimer J. L., Mallet A., Golmard J. L., Boisvieux J. F. Alternative approaches to estimation of population pharmacokinetic parameters: comparison with the nonlinear mixed-effect model. Drug Metab Rev. 1984;15(1-2):265–292. doi: 10.3109/03602538409015066. [DOI] [PubMed] [Google Scholar]
  18. Steinijans V. W., Hartmann M., Huber R., Radtke H. W. Lack of pharmacokinetic interaction as an equivalence problem. Int J Clin Pharmacol Ther Toxicol. 1991 Aug;29(8):323–328. [PubMed] [Google Scholar]
  19. 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]
  20. Whittington R., Faulds D. Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer. Drugs. 1993 Sep;46(3):446–514. doi: 10.2165/00003495-199346030-00009. [DOI] [PubMed] [Google Scholar]
  21. Yamaoka K., Nakagawa T., Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm. 1978 Apr;6(2):165–175. doi: 10.1007/BF01117450. [DOI] [PubMed] [Google Scholar]

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

RESOURCES