       Document 0611
 DOCN  M9630611
 TI    Safety, pharmacokinetics, and antiviral activity of A77003, a C2
       symmetry-based human immunodeficiency virus protease inhibitor.
 DT    9603
 AU    Reedijk M; Boucher CA; van Bommel T; Ho DD; Tzeng TB; Sereni D; Veyssier
       P; Jurriaans S; Granneman R; Hsu A; et al; Department of Internal
       Medicine (Clinical AIDS Unit), University; of Amsterdam, The
       Netherlands.
 SO    Antimicrob Agents Chemother. 1995 Jul;39(7):1559-64. Unique Identifier :
       AIDSLINE MED/96104900
 AB    A77003, an inhibitor of the human immunodeficiency virus type 1 (HIV-1)
       protease, was administered to asymptomatic HIV-1-infected patients in a
       phase I trial. The drug was given by continuous intravenous infusion at
       dosages of 0.035, 0.07, 0.14, and 0.28 mg/kg of body weight per h. The
       drug was given first for 24 h and then for up to an additional 4 weeks
       in a second infusion period following at least a 6-day washout. Apart
       from reversible increases in hepatic transaminase levels in some
       patients, no systemic toxicities occurred during extended infusion of
       the drug. Dose-related local vein irritation, despite dilution of the
       infusate, however, caused severe infusion site phlebitis precluding
       dosage escalation beyond 0.28 mg/kg/h. Pharmacokinetic analysis
       demonstrated dose linear increases in mean steady-state concentrations.
       However, clearance of the drug from plasma was unexpectedly high,
       averaging 62 liters/h across all groups. The concentrations of A77003 in
       plasma achieved the in vitro 50% inhibitory concentration (0.16
       microgram/ml) only in the 0.28-mg/kg/h dosage group, but it did not
       attain the 90% inhibitory concentration (0.48 micrograms/ml). No
       statistically significant effect on CD4 cell numbers occurred in any of
       the groups, and there was no evidence of antiviral activity, as
       determined by HIV-1 p24 antigen level, quantitative plasma and cell
       culture, and quantitation of viral RNA in plasma. In conclusion, A77003,
       as formulated in the present study, causes severe phlebitis, which
       prevents administration of the infusates necessary to achieve high
       concentrations of the drug in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
 DE    Adolescence  Adult  Aged  CD4 Lymphocyte Count/DRUG EFFECTS
       Dose-Response Relationship, Drug  Female  Human  HIV Core Protein
       p24/BLOOD  HIV Infections/*DRUG THERAPY/ENZYMOLOGY/IMMUNOLOGY  HIV
       Protease Inhibitors/ADVERSE EFFECTS/*PHARMACOKINETICS/  *THERAPEUTIC USE
       HIV-1/ENZYMOLOGY  Infusions, Intravenous  Leukocytes,
       Mononuclear/VIROLOGY  Male  Methylurea Compounds/ADVERSE
       EFFECTS/*PHARMACOKINETICS/  *THERAPEUTIC USE  Middle Age
       Pyridines/ADVERSE EFFECTS/*PHARMACOKINETICS/*THERAPEUTIC USE  RNA,
       Viral/BLOOD  CLINICAL TRIAL  CLINICAL TRIAL, PHASE I  JOURNAL ARTICLE

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

