       Document 0811
 DOCN  M94B0811
 TI    Effect of 2',3'-didehydro-3'-deoxythymidine in an in vitro hollow-fiber
       pharmacodynamic model system correlates with results of dose-ranging
       clinical studies.
 DT    9412
 AU    Bilello JA; Bauer G; Dudley MN; Cole GA; Drusano GL; Department of
       Medicine, Albany Medical College, New York 12208.
 SO    Antimicrob Agents Chemother. 1994 Jun;38(6):1386-91. Unique Identifier :
       AIDSLINE MED/94379796
 AB    We sought to validate an in vitro system which could predict the minimal
       effect dose of antiretroviral agents. Mixtures of uninfected CEM cells
       and CEM cells chronically infected with human immunodeficiency virus
       (HIV) type 1 MN were exposed to 2',3'-didehydro-3'-deoxythymidine (D4T)
       in vitro in a hollow-fiber model which simulates the plasma
       concentration-time profile of D4T in patients. Drug concentration was
       adjusted to simulate continuous intravenous infusion, or an intravenous
       bolus administered twice daily. The effect of the dosing regimen was
       measured with viral infectivity, p24 antigen, and reverse transcriptase
       or PCR for unintegrated HIV DNA. Dose deescalation studies on a
       twice-daily dosing schedule predicted a minimum effect dose of 0.5 mg/kg
       of body weight per day which correlated with the results of a clinical
       trial. Antiviral effect was demonstrated to be independent of schedule
       for every 12-h dosing versus continuous infusion. Finally, at or near
       the minimal effect dose, efficacy appeared to depend on the viral load.
       The ability of this in vitro pharmacodynamic model to assess the
       response of HIV-infected cells to different doses and schedules of
       antiviral agents may be useful in the design of optimal dosing regimens
       for clinical trials but requires validation with other types of
       antiretroviral agents.
 DE    Cell Line  Dose-Response Relationship, Drug  DNA, Viral/ANALYSIS  Human
       HIV/*DRUG EFFECTS/GENETICS/PHYSIOLOGY  Models, Biological
       Stavudine/ADMINISTRATION & DOSAGE/*PHARMACOLOGY/PHARMACOKINETICS
       Support, Non-U.S. Gov't  Virus Replication/DRUG EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

