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

Abstract

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.

Cidofovir, a New Agent with Potent Anti-Herpesvirus Activity

“…The antiviral effect in urine was also maintained with probenecid present in the dosing regimen. Comparison of pooled data for dose groups of :2:3 mg kg-1 vs. < 3 mg kg-1 showed a statistically significant difference for antiviral response in both semen and urine (P < 0.005 for each, see Lalezari et al, 1995).…”

“…Data from Lalezari et al, 1995. 'A response in semen is a value for number of plaque forming units that is~1 DO-foldlower than the baseline value.…”

Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections

“…In clinical trials cidofovir has proven efficacious not only against CMV retinitis but also against other manifestations of CMV disease, e.g., intravenously against asymptomatic CMV infection in HIV-infected patients (121,165). Cidofovir can be recommended as a preemptive treatment for CMV disease (i.e., treatment initiated if CMV antigen or DNA is detected in the blood) after allogeneic blood stem cell transplantation (163).…”

Beneficial response of cervical dystonia spasmodic torticollis to cidofovir, an acyclic phosphonate analog (s-1-3-hydroxy-2- phosphonylmethoxypropyl) of cytosine

“…17 Further, cidofovir enters both herpesvirus-infected and noninfected cells, unlike valganciclovir, valaciclovir, and famciclovir, which only enter infected cells. Cidofovir rapidly inhibits further spread of infection.…”