title: Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients.
abstract: 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.
authors.affiliation: Gilead Sciences, Inc., Foster City, California 94404, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Cundy
authors.forename: B G
authors.initials: BG
authors.lastname: Petty
authors.forename: J
authors.initials: J
authors.lastname: Flaherty
authors.forename: P E
authors.initials: PE
authors.lastname: Fisher
authors.forename: M A
authors.initials: MA
authors.lastname: Polis
authors.forename: M
authors.initials: M
authors.lastname: Wachsman
authors.forename: P S
authors.initials: PS
authors.lastname: Lietman
authors.forename: J P
authors.initials: JP
authors.lastname: Lalezari
authors.forename: M J
authors.initials: MJ
authors.lastname: Hitchcock
authors.forename: H S
authors.initials: HS
authors.lastname: Jaffe
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D000077404:Cidofovir; D003586:Cytomegalovirus Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D016867:Immunocompromised Host; D007668:Kidney / Q000378:metabolism; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir; D011339:Probenecid