1. Relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials.
- Author
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Flexner C, van der Horst C, Jacobson MA, Powderly W, Duncanson F, Ganes D, Barditch-Crovo PA, Petty BG, Baron PA, and Armstrong D
- Subjects
- Adult, Aged, Antiviral Agents administration & dosage, Antiviral Agents therapeutic use, CD4 Lymphocyte Count drug effects, Dideoxynucleosides administration & dosage, Dideoxynucleosides therapeutic use, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, HIV Core Protein p24 blood, Humans, Male, Middle Aged, Prospective Studies, Antiviral Agents blood, Dideoxynucleosides blood, HIV drug effects, HIV Infections drug therapy
- Abstract
Two concentration-controlled trials (CCTs) defined the relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and changes in surrogate markers of antiretroviral activity. In an initial open-label CCT involving 14 subjects infected with human immunodeficiency virus (HIV), unacceptable hematologic toxicity occurred when the area under the concentration-time curve during a 12-h dosing interval (AUC12) was > or = 300 ng*h/mL. Consequently, 46 subjects were assigned to AUC12s of 50, 100, or 200 ng*h/mL for up to 16 weeks in a prospective, randomized, double-blind CCT. Alovudine caused a concentration-dependent reduction in p24 antigen and peripheral blood mononuclear cell HIV titers within 4 weeks of start of treatment. The AUC12 producing a 50% reduction in p24 (108 ng*h/mL) had a trough concentration identical to the reported IC50 of alovudine in HIV-infected H9 cells. It may be possible to predict the antiretroviral activity of certain nucleoside analogues as a function of plasma drug concentration.
- Published
- 1994
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