Document 1084
 DOCN  M9591084
 TI    Safety, tolerance, and pharmacokinetics of atevirdine mesylate
       (U-87201E) in asymptomatic human immunodeficiency virus-infected
       patients.
 DT    9509
 AU    Been-Tiktak AM; Vrehen HM; Schneider MM; van der Feltz M; Branger T;
       Ward P; Cox SR; Harry JD; Borleffs JC; Department of Internal Medicine,
       University Hospital Utrecht, The; Netherlands.
 SO    Antimicrob Agents Chemother. 1995 Mar;39(3):602-7. Unique Identifier :
       AIDSLINE MED/95314189
 AB    Atevirdine mesylate (U-87201E) is a new nonnucleoside
       (bisheteroarylpiperazine) inhibitor of human immunodeficiency virus type
       1 reverse transcriptase. In a double-blind, escalating single-dose study
       the safety, tolerance, and pharmacokinetics of atevirdine mesylate were
       investigated in 24 asymptomatic human immunodeficiency
       virus-seropositive male patients. Each patient received one single oral
       dose of atevirdine mesylate and placebo separated by an interval of 1 to
       3 weeks. For each dose level (400, 800, 1,200, and 1,600 mg) six
       patients received drug and placebo on separate occasions. Blood samples
       were collected before dosing and at intervals afterward for safety
       evaluation and estimation of atevirdine and metabolite levels. The
       concentrations of atevirdine and its principal metabolite (U-89255) in
       serum were determined by high-performance liquid chromatography. The
       results of the study showed that atevirdine mesylate is well tolerated
       at all dose levels. No clinically significant effects on vital signs,
       electrocardiograms, or laboratory tests were observed. Occasional
       headache and nausea were reported both in the drug group and in the
       placebo group. The times to peak values were relatively short (0.5 to
       1.0 h), suggesting a rapid absorption. The maximum concentrations of
       drug in serum were 1.4 microM (400 mg), 4.2 microM (800 mg), 7.3 microM
       (1,200 mg), and 5.8 microM (1,600 mg). The values of the pharmacokinetic
       parameters for atevirdine were found to have relatively large
       intersubject variabilities, and consequently, the study had little power
       to detect dose-dependent changes in the values of the pharmacokinetic
       parameters. The oral clearance of atevirdine tended to increase by 90%
       as the atevirdine mesylate doses increased from 400 to 1,600 mg, but
       this change in oral clearance was not statistically significant. The
       values of the pharmacokinetic parameters determined in the study were
       similar to those found in a previous single-dose study in healthy
       volunteers.
 DE    Adult  Antiviral Agents/*ADVERSE EFFECTS/*PHARMACOKINETICS  Double-Blind
       Method  Human  HIV Seropositivity/*METABOLISM  *HIV-1  Male  Middle Age
       Piperazines/*ADVERSE EFFECTS/*PHARMACOKINETICS  CLINICAL TRIAL  JOURNAL
       ARTICLE  RANDOMIZED CONTROLLED TRIAL

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