Advertisement

Journal of Pharmacokinetics and Biopharmaceutics

, Volume 25, Issue 6, pp 713–730 | Cite as

A Pharmacokinetic–Pharmacodynamic Model of Chemotherapy of Human Immunodeficiency Virus Infection that Relates Development of Drug Resistance to Treatment Intensity

  • Robert C. Jackson
Article

Abstract

RNA viruses, including relrovimses. have Mutation rates that are about 100 limes higher than those of DNA viruses, bacteria, or eukaryotes, so that resistance to AIDS drugs emerges very rapidly. This has been shown to limil the effectiveness of the treatment of AIDS by reverse transcriptase inhibitors, such as zidovudine (AZT) and resistance to the new class of HIV aspartyl protease inhibitors has already been reported. The technique of pharmacokinetic–pharmacodynamic simulation has now been used to predict ways of delaying the development of resistance to these two classes of antiretroviral agents. A model is described that includes pharmacokinetic, pharmacodynamic, and cytokinetic equations, and expressions describing effects of the HIV on the immune system and destruction of virally infected cells by cellular immunity. The model predicted that the degree of viral drug resistance in relation to ike sustainable blood level of drug would be the major determinant of response duration. Early treatment was consistently superior to late treatment, both with a drug that caused cumulative loxicity and with a drug that did not. Making reasonable assumptions about the likely degree of viral resistance, in conjunction with typical blood levels achievable for reverse transcriptase inhibitors or aspartyl protease inhibitors led to predicted response durations of several months to a few years, despite the rapid mutation rate of HIV. Preliminary studies of combination chemotherapy showed that predicted response durations were greater than for monotherapy, though less than the sum of responses to the individual drugs. Strategies for delaying the development of resistance include early treatment, combination chemotherapy, and developing novel agents with a high ratio of plasma level to antiviral efficacy.

AIDS cytokinetic model drug resistance HIV protease inhibitor nelfinavir pharmacodynamic model pharmacokinetic model reverse transcriptase inhibitor zidovudine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    D. D. Richman. HIV drug resistance. Ann. Rev. Pharmacol. Toxicol. 32:149–164 (1993).CrossRefGoogle Scholar
  2. 2.
    P. S. Sarin. Molecular pharmacologic approaches to the treatment of AIDS. Ann. Rev. Pharmacol. Toxicol. 28:411–428 (1988).CrossRefGoogle Scholar
  3. 3.
    T. Ridky and J. Leis. Development of drug resistance to HIV-1 protease inhibitors. J. Biol. Chem. 270:29261–29263 (1995).CrossRefGoogle Scholar
  4. 4.
    A. R. McLean, V. C. Emery, A. Webster, and P. D. Griffiths. Population dynamics of HIV within an individual after treatment with zidovudine. AIDS 5:485–489 (1991).PubMedCrossRefGoogle Scholar
  5. 5.
    R. A. Weiss. How does HIV cause AIDS? Science 260:1273–1279 (1993).PubMedCrossRefGoogle Scholar
  6. 6.
    M. A. Nowack, R. M. Anderson, A. R. McLean, T. F. W. Wolfs, J. Goudsmit, and R. M. May. Antigenic diversity thresholds and the development of AIDS. Science 254:963–969 (1991).CrossRefGoogle Scholar
  7. 7.
    M. A. Nowack and R. M. May. Mathematical biology of HIV infections: antigenic variation and diversity threshold. Math. Biosci. 106:1–21 (1991).CrossRefGoogle Scholar
  8. 8.
    M. A. Nowack and R. M. May. Coexistence and competition in HIV infections. J. Theoret. Biol. 159:329–342 (1992).CrossRefGoogle Scholar
  9. 9.
    P. G. Welling. Pharmacokinetics: Processes and Mathematics, American Chemical Society, Washington, DC, 1986, p. 165.Google Scholar
  10. 10.
    A. V. Hill. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J. Physiol. (London) 40:4–16 (1910).Google Scholar
  11. 11.
    T.-C. Chou and P. Talalay. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Reg. 22:27–55 (1984).CrossRefGoogle Scholar
  12. 12.
    S. E. Luria and M. Delbrück. Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28:491–511 (1943).PubMedCentralPubMedGoogle Scholar
  13. 13.
    M. Eigen. Viral quasispecies. Sci. Am. 269:42–49 (1993).PubMedCrossRefGoogle Scholar
  14. 14.
    J. M. Coffin. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267:483–489 (1995).PubMedCrossRefGoogle Scholar
  15. 15.
    W. H. Press, B. P. Flannery, S. A. Teukolsky, and W. T. Vetterling. Numerical Recipes in C: The Art of Scientific Programming, Cambridge University Press, Cambridge, U.K., 1988.Google Scholar
  16. 16.
    B. Shetty, M. B. Kosa, D. A. Khalil, and S. Webber. Preclinical pharmacokinetics and distribution to tissue of AG-1343, an inhibitor of numan immunodeficiency virus type 1 protease. Antimicrob. Agents Chemother. 40:110–114 (1996).PubMedCentralPubMedGoogle Scholar
  17. 17.
    X. Wei, S. K. Ghosh, M. E. Taylor, et al. Viral dynamics in human immunodeficiency type I infection. Nature 373:117–122 (1995).PubMedCrossRefGoogle Scholar
  18. 18.
    D. D. Ho, A. U. Neumann, A. S. Perelson, W. Chen, J. M. Leonard, and M. Markowitz. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123–126 (1995).PubMedCrossRefGoogle Scholar
  19. 19.
    A. N. Phillips. Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271:497–499 (1996).PubMedCrossRefGoogle Scholar
  20. 20.
    A. K. Patick, H. Mo, M. Markowitz, K. Appelt, B. Wu, L. Musick, V. Kalish, S. Kaldor, S. Reich, D. Ho, and S. Webber. Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease. Antimicrob. Agents Chemother. 40:292–297 (1996).PubMedCentralPubMedGoogle Scholar
  21. 21.
    J. P. Sommadossi and R. Carlisle. Toxicity of 3′-azido-3′-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine in normal human hematopoietic progenitor cels in vitro. Antimicrob. Agents Chemother. 31:452–454 (1987).PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    H. E. Skipper, F. M. Schabel, and W. S. Wilcox. Experimental evaluation of potential anticancer agents. XIII. On the criteria and kinetics associated with curability of experimental leukemia. Cancer Chemother. Rep. 35:1–111 (1964).PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1997

Authors and Affiliations

  • Robert C. Jackson
    • 1
  1. 1.Agouron Pharmaceuticals, Inc.San Diego

Personalised recommendations