Document 0029
 DOCN  M9610029
 TI    Clinical pharmacokinetics of cidofovir in human immunodeficiency
       virus-infected patients.
 DT    9601
 AU    Cundy KC; Petty BG; Flaherty J; Fisher PE; Polis MA; Wachsman M; Lietman
       PS; Lalezari JP; Hitchcock MJ; Jaffe HS; Gilead Sciences, Inc., Foster
       City, California 94404, USA.
 SO    Antimicrob Agents Chemother. 1995 Jun;39(6):1247-52. Unique Identifier :
       AIDSLINE MED/96012180
 AB    The pharmacokinetics of cidofovir (HPMPC;
       (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at
       five dose levels in three phase I/II studies in a total of 42 human
       immunodeficiency virus-infected patients (with or without asymptomatic
       cytomegalovirus infection). Levels of cidofovir in serum following
       intravenous infusion were dose proportional over the dose range of 1.0
       to 10.0 mg/kg of body weight and declined biexponentially with an
       overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 h
       (n = 25). Approximately 90% of the intravenous dose was recovered
       unchanged in the urine in 24 h. The overall mean +/- standard deviation
       total clearance of the drug from serum (148 +/- 25 ml/h/kg; n = 25)
       approximated renal clearance (129 +/- 42 ml/h/kg; n = 25), which was
       significantly higher (P < 0.001) than the baseline creatinine clearance
       in the same patients (83 +/- 21 ml/h/kg; n = 12). These data indicate
       that active tubular secretion played a significant role in the clearance
       of cidofovir. The steady-state volume of distribution of cidofovir was
       approximately 500 ml/kg, suggesting that the drug was distributed in
       total body water. Repeated dosing with cidofovir at 3.0 and 10.0
       mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant
       administration of intravenous cidofovir and oral probenecid to hydrated
       patients had no significant effect on the pharmacokinetics of cidofovir
       at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to
       block tubular secretion of cidofovir and reduce its renal clearance to a
       level approaching glomerular filtration.
 DE    Adult  Antiviral Agents/ADMINISTRATION & DOSAGE/ANALYSIS/
       *PHARMACOKINETICS  AIDS-Related Opportunistic
       Infections/COMPLICATIONS/DRUG THERAPY/  METABOLISM  Cytomegalovirus
       Infections/COMPLICATIONS/DRUG THERAPY/METABOLISM  Cytosine/*ANALOGS &
       DERIVATIVES/ADMINISTRATION & DOSAGE/ANALYSIS/  PHARMACOKINETICS
       Dose-Response Relationship, Drug  Drug Therapy, Combination  Female
       Human  HIV Infections/COMPLICATIONS/DRUG THERAPY/*METABOLISM
       *Immunocompromised Host  Kidney/METABOLISM  Kidney Function Tests  Male
       Metabolic Clearance Rate  Middle Age  Organophosphorus
       Compounds/ADMINISTRATION & DOSAGE/ANALYSIS/  *PHARMACOKINETICS
       Probenecid/ADMINISTRATION & DOSAGE/PHARMACOLOGY  JOURNAL ARTICLE

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