Relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials.
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.
Flexner
C
C
Johns Hopkins University School of Medicine, Baltimore, Maryland.
van der Horst
C
C
Jacobson
M A
MA
Powderly
W
W
Duncanson
F
F
Ganes
D
D
Barditch-Crovo
P A
PA
Petty
B G
BG
Baron
P A
PA
Armstrong
D
D
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count / Q000187:drug effects; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006678:HIV / Q000187:drug effects*; D016655:HIV Core Protein p24 / Q000097:blood; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D016655:HIV Core Protein p24; C002854:alovudine