Fomivirsen
Fomivirsen Uses, Dosage, Side Effects, Food Interaction and all others data.
Fomivirsen is a antisense 21 mer phosphorothioate oligonucleotide. It is an antiviral agent that was used in the treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients, including those with AIDS. As a complementary nucleotide to the messenger RNA of the major immediate-early region proteins of human cytomegalovirus, it disrupts the replication of the virus through an antisense mechanism . It was discovered by scientists at the National Institutes of Health (NIH) and was first developed by Isis Pharmaceuticals and subsequently licensed to Novartis . The drug was withdrawn by the FDA because while there was a high unmet need for drugs to treat CMV when the drug was initially discovered and developed due to the CMV arising in people with AIDS, the development of HAART dramatically reduced the number of cases of CMV. Fomivirsen is marketed under the trade name Vitravene for intravitreal injection and was the first antisense drug to be approved by the Food and Drug Administration (FDA).
Fomivirsen is an antiviral agent that inhibits CMV replication in a dose-dependent manner with a mean 50% inhibitory concentration between 0.03 and 0.2 μM in a number of in vitro cell lines . In human fibroblast cell lines, the median effective inhibitory concentration (EC50) of fomivirsen for virus antigen production was approximately 0.34±0.25 μM . In a clinical trial, administration of fomivirsen in patients with newly diagnosed CMV retinitis resulted in an increased median time to disease progression in the immediate treatment group versus delayed treatment group .
| Trade Name | Fomivirsen |
| Generic | Fomivirsen |
| Fomivirsen Other Names | Fomivirsen |
| Type | Intraocular |
| Protein binding | Fomivirsen is approximately 40% bound to proteins according to the analysis of vitreous samples from treated rabbits and monkeys . It is mostly bound to albumin and alpha2-macroglobulin in blood plasma . |
| Groups | Approved, Investigational, Withdrawn |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Indicated for the local treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS), when other therapy has been ineffective or is considered unsuitable .
How Fomivirsen works
Fomivirsen is a phosphorothioate oligonucleotide that inhibits the replication of human cytomegalovirus (HCMV) through an antisense mechanism. The nucleotide sequence is complementary to a sequence in mRNA transcripts of the major immediate early region 2 (IE2) of human CMV, which encodes several proteins responsible for regulation of viral gene expression that are essential for viral replication . The IE2 gene is essential for early viral gene expression and viral replication ; it was shown that the IE2 gene transactivate most human CMV promoters . Protein product from the IE2 region also acts as autorepressor that represses transcription of the IE1 and IE2 genes by binding the cis repression sequence (CRS) . It is proposed that the IE2 region interacts with multiple basal and general transcription factors, as well as cell cycle regulators, and it also plays a critical role in controlling the entry of the virus into the lytic cycle from the latent state to further potentiate the infection cascade . Upon binding to the target mRNA, fomivirsen inhibits the IE2 protein synthesis and disrupts viral replication .
Toxicity
There has been one case of accidental overdose of fomivirsen with administration once bilaterally with 990 μg per eye; vision was restored with anterior chamber paracentesis performed bilaterally . According to the findings in Salmonella/Microsome (Ames) and mouse lymphoma tests, fomivirsen was not shown to be mutagenic. In the in vivo mouse micronucleus assay, fomivirsen was not clastogenic. Animal reproductive studies or studies evaluating the carcinogenic potential of fomivirsen has not been conducted .
Volume of Distribution
Preclinical studies show that fomivirsen distributes to retina .
Elimination Route
Following intravitreal injection in rabbits and monkeys, peak concentrations in the vitreous was detectable immediately after injection with the concentrations increasing in a dose-proportional manner . Due to low doses of intravitreal administration with slow disposition from the eye, there is limited absorption of the drug into the systemic circulation . Fomivirsen is detectable in retina of rabbits within hours following administration and concentrations increase over 3 to 5 days. The concentrations of the drug were highest in the retina and iris .
Half Life
Intravitreal drug clearance studies have revealed first-order kinetics . Following intravitreal administration, fomivirsen is slowly cleared from vitreous with a half-life of approximately 55 hours in humans . The half life from retina in monkeys following administration of 115 mcg fomivirsen is estimated to be 78 hours .
Clearance
Clearance from retina was shown to be similarly slow following loading from the vitreous .
Elimination Route
In rabbits, 16% of total radiolabelled fomivirsen was detected in urine and 3% was detected in feces .
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