Document 1057
 DOCN  M9651057
 TI    Clinical pharmacokinetics of adefovir in human immunodeficiency virus
       type 1-infected patients.
 DT    9505
 AU    Cundy KC; Barditch-Crovo P; Walker RE; Collier AC; Ebeling D; Toole J;
       Jaffe HS; Gilead Sciences, Inc., Foster City, California 94404, USA.
 SO    Antimicrob Agents Chemother. 1995 Nov;39(11):2401-5. Unique Identifier :
       AIDSLINE MED/96139529
 AB    The pharmacokinetics and bioavailability of adefovir
       [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels
       in three phase I/II studies in 28 human immunodeficiency type 1-infected
       patients. The concentrations of adefovir in serum following the
       intravenous infusion of 1.0 or 3.0 mg/kg of body weight were dose
       proportional and declined biexponentially, with an overall mean +/-
       standard deviation terminal half-life of 1.6 +/- 0.5 h (n = 28).
       Approximately 90% of the intravenous dose was recovered unchanged in the
       urine in 12 h, and more than 98% was recovered by 24 h postdosing. The
       overall mean +/- standard deviation total serum clearance of the drug
       (223 +/- 53 ml/h/kg; n = 25) approximated the renal clearance (205 +/-
       78 ml/h/kg; n = 20), which was significantly higher (P < 0.01) than the
       baseline creatinine clearance in the same patients (88 +/- 18 ml/h/kg; n
       = 25). Since adefovir is essentially completely unbound in plasma or
       serum, these data indicate that active tubular secretion accounted for
       approximately 60% of the clearance of adefovir. The steady-state volume
       of distribution of adefovir (418 +/- 76 ml/kg; n = 28) suggests that the
       drug was distributed in total body water. Repeated daily dosing with
       adefovir at 1.0 mg/kg/day (n = 8) and 3.0 mg/kg/day (n = 4) for 22 days
       did not significantly alter the pharmacokinetics of the drug; there was
       no evidence of accumulation. The oral bioavailability of adefovir at a
       3.0-mg/kg dose was < 12% (n = 5) on the basis of the concentrations in
       serum or 16.4% +/- 16.0% on the basis of urinary recovery. The
       subcutaneous bioavailability of adefovir at a 3.0-mg/kg dose was 102%
       +/- 8.3% (n = 5) on the basis of concentrations in serum or 84.8% +/-
       28.5% on the basis of urinary recovery. These data are consistent with
       preclinical observations in various species.
 DE    Adenine/*ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/
       PHARMACOKINETICS  Administration, Oral  Adult  Antiviral
       Agents/ADMINISTRATION & DOSAGE/*PHARMACOKINETICS  Biological
       Availability  Female  Half-Life  Human  HIV Infections/DRUG
       THERAPY/*METABOLISM/VIROLOGY  *HIV-1  Injections, Intravenous
       Injections, Subcutaneous  Male  Middle Age  Protein Binding  Support,
       U.S. Gov't, P.H.S.  CLINICAL TRIAL  JOURNAL ARTICLE

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