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Mechanism of Action
Fomivirsen is a phosphorothioate oligonucleotide that inhibits human cytomegalovirus (HCMV) replication through an antisense mechanism. The nucleotide sequence of fomivirsen is complementary to a sequence in mRNA transcripts of the major immediate early region 2 (IE2) of HCMV. This region of mRNA encodes several proteins responsible for regulation of viral gene expression that are essential for production of infectious CMV. Binding of fomivirsen to the target mRNA, results in inhibition of IE2 protein synthesis, subsequently inhibiting virus replication.
Through persistent selection pressure in vitro it was possible to isolate a clone of HCMV that was 10-fold less sensitive to inhibition of replication than the parent strain. The molecular basis for the resistance has not been elucidated. It is possible that resistant strains may occur in clinical use.
The antisense mechanism of action and molecular target of fomivirsen are different from that of inhibitors of HCMV replication, which function by inhibiting the viral DNA polymerase. Fomivirsen was equally potent against 21 independent clinical HCMV isolates, including several that were resistant to ganciclovir, foscarnet and/or cidofovir. Isolates, which are resistant to fomivirsen, may be sensitive to ganciclovir, foscarnet and/or cidofovir.
The assessment of ocular pharmacokinetic parameters in patients has been limited and is still ongoing.
Ocular Kinetics: Fomivirsen is cleared from the vitreous in rabbits over the course of 7 to 10 days, by a combination of tissue distribution and metabolism. In the eye, fomivirsen concentrations were greatest in the retina and iris. Fomivirsen was detectable in retina within hours after injection, and concentrations increased over 3 to 5 days.
Metabolism and Elimination: Metabolism is the primary route of elimination from the eye. Metabolites of fomivirsen are detected in the retina and vitreous in animals. Fomivirsen sodium is metabolized by exonucleases in a process that sequentially removes residues from the terminal ends of the oligonucleotide yielding shortened oligonucleotides and mononucleotide metabolites. Data with related compounds indicate that mononucleotide metabolites are further catabolized similar to endogenous nucleotides and are excreted as low molecular weight metabolites. In rabbits, a small amount of fomivirsen-derived radioactivity was eliminated in urine (16%) or feces (3%) as low molecular weight metabolites. Expired air has been shown to be a major route of excretion for CO 2 generated by catabolism of nucleotides after administration of phosphorothioate oligonucleotides.
Systemic Exposure: Systemic exposure to fomivirsen following single or repeated intravitreal injection in monkeys was below limits of quantitation (70 [ng ]g/mL in plasma and 350 [ng ]g/g in tissue). In monkeys treated every other week for up to 3 months with fomivirsen there were isolated instances when fomivirsen's metabolites were observed in liver, kidney, and plasma at a concentration near the level of detection (14 [ng ]g/mL in plasma and 70 [ng ]g/g in tissue).
Protein Binding: Analysis of vitreous samples from treated rabbits and monkeys indicates that approximately 40% of fomivirsen is bound to proteins.
Clinical ocular pharmacokinetics studies have not yet been completed.
Limited, open label, controlled clinical studies evaluating the safety and efficacy of Vitravene (fomivirsen) † have been conducted in patients with newly diagnosed CMV retinitis and in patients who have failed previous therapies. Based on the assessment of fundus photographs, the median time to CMV retinitis progression was approximately 80 days in patients receiving a dose of 330 µg. Many of these patients were also receiving protease inhibitor treatment. In the subgroup of newly diagnosed patients who received delayed treatment, most had CMV retinitis progression within two weeks. Head to head comparisons with other medications available to treat CMV retinitis has not been completed.
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
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