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General Description:

Fomivirsen, identified by CAS number 144245-52-3, is a notable compound with significant therapeutic applications. 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 The drug was withdrawn by the FDA because while there was a high unmet need for drugs to treat CMV when the drug was initially discovered and developed due to the CMV arising in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).

Indications:

This drug is primarily indicated for: 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 . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Fomivirsen undergoes metabolic processing primarily in: Fomivirsen undergoes metabolism mediated by endo- and exonuclease, where the resides from the terminal ends of the oligonucleotide are sequentially removed . Resulting shortened oligonucleotides and mononucleotide metabolites can be detected in the retina and vitreous of animals . Mononucleotides may also be further catabolized to endogenous nucleotides and excreted as low molecular weight metabolites . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Fomivirsen are crucial for its therapeutic efficacy: 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 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Fomivirsen is an important consideration for its dosing schedule: 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 . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Fomivirsen exhibits a strong affinity for binding with plasma proteins: 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 . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Fomivirsen from the body primarily occurs through: In rabbits, 16% of total radiolabelled fomivirsen was detected in urine and 3% was detected in feces . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Fomivirsen is distributed throughout the body with a volume of distribution of: Preclinical studies show that fomivirsen distributes to retina . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Fomivirsen is a critical factor in determining its safe and effective dosage: Clearance from retina was shown to be similarly slow following loading from the vitreous . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Fomivirsen exerts its therapeutic effects through: 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 . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Fomivirsen functions by: 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Fomivirsen is categorized under the following therapeutic classes: Anti-Infective Agents, Antisense Elements (Genetics), Antisense Oligonucleotides, Antiviral Agents, Compounds used in a research, industrial, or household setting, Laboratory Chemicals, Molecular Probes, Nucleic Acid Probes, Nucleic Acids, Nucleic Acids, Nucleotides, and Nucleosides, Nucleotides, Oligonucleotides, Ophthalmologicals, Polynucleotides, Sensory Organs, Sulfur Compounds. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Fomivirsen include:

• Molecular Weight: 7122.0
• Molecular Formula: C204H243N63O114P20S20Na20