(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (cidofovir): results of a phase I/II study of a novel antiviral nucleotide analogue.
Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, is a novel antiviral nucleotide analogue with potent in vitro and in vivo activity against cytomegalovirus (CMV) and other herpesviruses. Thirty-one human immunodeficiency virus-seropositive patients with asymptomatic CMV excretion were evaluated in a phase I/II study with 2 regimens of cidofovir: cidofovir alone at doses of 0.5, 1.0, 3.0, or 10.0 mg/kg/week (20 patients) and cidofovir at 3.0, 5.0, or 7.5 mg/kg with concomitant oral probenecid, saline prehydration, extended dosing intervals, and drug interruption for proteinuria (19 patients). Prolonged and dose-dependent anti-CMV effect was observed with all cidofovir regimens > or = 3.0 mg/kg. The dose-limiting toxicity of cidofovir was dose- and schedule-dependent nephrotoxicity. Four of 20 patients had serum creatinine levels > or = 2.0 mg/dL after a mean cumulative exposure of 14.8 mg/kg cidofovir alone; however, none of 19 patients receiving the modified regimen had elevated creatinine (mean cidofovir exposure, 32.2 mg/kg). The clinical efficacy of cidofovir and its potential for cumulative nephrotoxicity needs further study in patients with end-organ CMV disease.
Lalezari
J P
JP
Department of Medicine, Mount Zion Medical Center, University of California, San Francisco 94115.
Drew
W L
WL
Glutzer
E
E
James
C
C
Miner
D
D
Flaherty
J
J
Fisher
P E
PE
Cundy
K
K
Hannigan
J
J
Martin
J C
JC
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy*; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077404:Cidofovir; D003401:Creatine / Q000097:blood; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D003596:Cytosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004279:DNA, Viral / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011339:Probenecid / Q000008:administration & dosage / Q000009:adverse effects; D011507:Proteinuria; D012661:Semen / Q000821:virology; D017201:Virus Shedding
D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir; D003401:Creatine; D011339:Probenecid