Virology

Ganciclovir is a synthetic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Sensitive human viruses include cytomegalovirus (CMV), herpes simplex virus -1 and -2 (HSV-1, HSV-2), Epstein-Barr virus (EBV) and varicella zoster virus (VZV). Clinical studies have been limited to assessment of efficacy in patients with CMV infection.

Median effective inhibitory doses (ED ₅₀ ) of ganciclovir for human CMV isolates tested in vitro in several cell lines ranged from 0.2 to 3.0 µg/mL. The relationship between in vitro sensitivity of CMV to ganciclovir and clinical response has not been established. Ganciclovir inhibits mammalian cell proliferation in vitro at higher concentrations (10 to 60 µg/mL) with bone marrow colony forming cells being the most sensitive (ID ₅₀ >=10 µg/mL) of those cell types tested.

Emergence of viral resistance has been reported based on in vitro sensitivity testing of CMV isolates from patients receiving intravenous ganciclovir treatment. The prevalence of resistant isolates is unknown, and there is a possibility that some patients may be infected with strains of CMV resistant to ganciclovir. Therefore, the possibility of viral resistance should be considered in patients who show poor clinical response.

Pharmacokinetics

In a clinical trial of Vitrasert Implants, 26 patients (30 eyes) received a total of 39 primary implants and 12 exchange implants (performed 32 weeks after the implant was inserted or earlier if progression of CMV retinitis occurred). Because most of the exchanged implants were empty, the time the implant actually ran out of drug was unknown, and a precise in-vivo release rate could not be calculated. However, approximate in-vivo release rates could be determined for the exchanged implants, which ranged from 1.00 µg/h to more than 1.62 µg/h.

In 14 implants (3 exchanged, 11 autopsy) in which the in-vivo release rate could accurately be calculated, the mean release rate was 1.40 µg/h, with a range from 0.5 to 2.88 µg/h. The mean vitreous drug levels in eight eyes (4 collected at the time of retinal detachment surgery; 2 collected from autopsy eyes within 6 hours of death and prior to fixation; 2 collected from implant exchanges) was 4.1 µg/mL.

Clinical Trials

In a randomized, controlled parallel group trial conducted between May 1993 and December 1994, treatment with the Vitrasert Implant was compared to treatment with intravenous ganciclovir (Cytovene-IV; Roche) in 188 patients with AIDS and newly diagnosed CMV retinitis. Patients randomized to the Cytovene-IV treatment group received Cytovene-IV solution at induction doses (5 mg/kg twice daily) for 14 days, followed by maintenance dosing (5 mg/kg once daily). Based on masked assessment of fundus photographs, the median time to progression was approximately 210 days for the Vitrasert Implant treatment group compared to approximately 120 days for the intravenous ganciclovir treatment group.

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