VISTIDE® is the brand name for cidofovir injection. The chemical name of cidofovir is 1-[( S )-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (HPMPC), with the molecular formula of C ₈ H ₁₄ N ₃ O ₆ P·2H ₂ O and a molecular weight of 315.22 (279.19 for anhydrous). The chemical structure is:

Cidofovir is a white crystalline powder with an aqueous solubility of ≥170 mg/mL at pH 6-8 and a log P (octanol/aqueous buffer, pH 7.1) value of -3.3.

VISTIDE is a sterile, hypertonic aqueous solution for intravenous infusion only. The solution is clear and colorless. It is supplied in clear glass vials, each containing 375 mg of anhydrous cidofovir in 5 mL aqueous solution at a concentration of 75 mg/mL. The formulation is pH-adjusted to 7.4 with sodium hydroxide and/or hydrochloric acid and contains no preservatives. The appropriate volume of VISTIDE must be removed from the single-use vial and diluted prior to administration (see DOSAGE AND ADMINISTRATION ).

MICROBIOLOGY

Mechanism of Action :   Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis. Biochemical data support selective inhibition of CMV DNA polymerase by cidofovir diphosphate, the active intracellular metabolite of cidofovir. Cidofovir diphosphate inhibits herpesvirus polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerase alpha, beta, and gamma ^1,2,3 . Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.

In Vitro Susceptibility :   Cidofovir is active in vitro against a variety of laboratory and clinical isolates of CMV and other herpesviruses (Table 1). Controlled clinical studies of efficacy have been limited to patients with AIDS and CMV retinitis.

Resistance :   CMV isolates with reduced susceptibility to cidofovir have been selected in vitro in the presence of high concentrations of cidofovir ⁴ . IC ₅₀ values for selected resistant isolates ranged from 7-15 µM.

There are insufficient data at this time to assess the frequency or the clinical significance of the development of resistant isolates following VISTIDE administration to patients.

The possibility of viral resistance should be considered for patients who show a poor clinical response or experience recurrent retinitis progression during therapy.

Cross Resistance :   Cidofovir-resistant isolates selected in vitro following exposure to increasing concentrations of cidofovir were assessed for susceptibility to ganciclovir and foscarnet ⁴ . All were cross resistant to ganciclovir, but remained susceptible to foscarnet. Ganciclovir- or ganciclovir/foscarnet-resistant isolates that are cross resistant to cidofovir have been obtained from drug naive patients and from patients following ganciclovir or ganciclovir/foscarnet therapy. To date, the majority of ganciclovir-resistant isolates are UL97 gene product (phosphokinase) mutants and remain susceptible to cidofovir ⁵ . Reduced susceptibility to cidofovir, however, has been reported for DNA polymerase mutants of CMV which are resistant to ganciclovir ^6-9 . To date, all clinical isolates which exhibit high level resistance to ganciclovir, due to mutations in both the DNA polymerase and UL97 genes, have been shown to be cross resistant to cidofovir. Cidofovir is active against some, but not all, CMV isolates which are resistant to foscarnet ^10-12 . The incidence of foscarnet-resistant isolates that are resistant to cidofovir is not known.

A few triple-drug resistant isolates have been described. Genotypic analysis of two of these triple-resistant isolates revealed several point mutations in the CMV DNA polymerase gene. The clinical significance of the development of these cross-resistant isolates is not known.

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