Concentration-controlled zidovudine therapy

Courtney V. Fletcher, Edward P. Acosta, Keith Henry, Linda M. Page, Cynthia R. Gross, Sagar P. Kawle, Rory P. Remmel, Alejo Erice, Henry H. Balfour

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Background: Heterogeneity in the response to antiretroviral therapy has been attributed to pharmacologic, immunologic, and virologic differences between patients. Currently available antiretroviral agents used for the treatment of human immunodeficiency virus (HIV) infection in adults are administered in standard fixed doses. The active moiety of nucleoside anti- HIV drugs is the intracellular anabolite. Therefore the heterogeneity in response to nucleoside agents may arise as a result of pharmacologic variability at both the systemic and cellular level. Objectives: To determine whether a novel concentration-controlled zidovudine regimen could improve anti-HIV response compared with the standard fixed-dose approach. Design: At the Outpatient Clinic of the General Clinical Research Center at the University of Minnesota, 20 persons with HIV infection received an oral regimen of zidovudine designed to achieve a target concentration in plasma of 0.7 μmol/L and the 500 mg/day standard dose in a randomized, crossover 24- week study. Results: The concentration-controlled regimen achieved overall higher systemic concentrations with reduced interpatient variability: steady- state average zidovudine plasma concentrations were 0.76 μmol/L (coefficient of variation, 12%) versus 0.62 μmol/L (coefficient of variation, 32%) for the standard regimen. There was no difference in safety and tolerance between regimens. Intracellular zidovudine triphosphate concentrations averaged 160 fmol/106 peripheral blood mononuclear cells (PBMCs) with concentration- controlled versus 92 fmol/106 PBMCs for standard therapy. The percentage change from baseline in CD4 cells was a 22% increase for the concentration- controlled regimen versus a 7% decrease with standard therapy. Conclusions: These data indicate that pharmacologic variability affects antiretroviral response. Furthermore, these findings provide a framework to characterize the pharmacologic determinants of effect and quantitate their contribution to the heterogeneity in clinical response to optimize therapeutic benefit.

Original languageEnglish (US)
Pages (from-to)331-338
Number of pages8
JournalClinical pharmacology and therapeutics
Volume64
Issue number3
DOIs
StatePublished - Sep 1 1998

Fingerprint Dive into the research topics of 'Concentration-controlled zidovudine therapy'. Together they form a unique fingerprint.

  • Cite this

    Fletcher, C. V., Acosta, E. P., Henry, K., Page, L. M., Gross, C. R., Kawle, S. P., Remmel, R. P., Erice, A., & Balfour, H. H. (1998). Concentration-controlled zidovudine therapy. Clinical pharmacology and therapeutics, 64(3), 331-338. https://doi.org/10.1016/S0009-9236(98)90182-5