(S)-1-[3-Hydroxy-2-(Phosphonylmethoxy)propyl]cytosine (Cidofovir): Results of a Phase I/II Study of a Novel Antiviral Nucleotide Analogue

• Published in: The Journal of infectious diseases 1995-04, Vol.171 (4), p.788-796
• Main Authors: Lalezari, J. P., Drew, W. L., Glutzer, E., James, C., Miner, D., Flaherty, J., Fisher, P. E., Cundy, K., Hannigan, J., Martin, J. C., Jaffe, H. S.
• Format: Article
• Language: English
• Subjects: Adult; AIDS; AIDS-Related Opportunistic Infections - drug therapy; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Antivirals; Cidofovir; Creatine - blood; Cytomegalovirus; Cytomegalovirus Infections - drug therapy; Cytosine - administration & dosage; Cytosine - adverse effects; Cytosine - analogs & derivatives; Cytosine - pharmacokinetics; Cytosine - therapeutic use; DNA, Viral - urine; Dosage; Dose-Response Relationship, Drug; Drug Therapy, Combination; Health care administration; Humans; Infections; Kidney - drug effects; Major Articles; Male; Middle Aged; Nephrotoxicity; Organophosphonates; Organophosphorus Compounds - administration & dosage; Organophosphorus Compounds - adverse effects; Organophosphorus Compounds - pharmacokinetics; Organophosphorus Compounds - therapeutic use; Pharmacokinetics; Probenecid - administration & dosage; Probenecid - adverse effects; Proteinuria; Semen - virology; Urine; Virus Shedding
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/171.4.788

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 Ijll 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 ⩾3.0 mg/kg. The dose-limiting toxicity of cidofovir was dose- and schedule-dependent nephrotoxicity. Four of20 patients had serum creatinine levels ⩾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 rug/kg). The clinical efficacyof cidofovir and its potential for cumulative nephrotoxicity needs further study in patients with end-organ CMV disease.