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General Description:

Vutrisiran, identified by CAS number 1867157-35-4, is a notable compound with significant therapeutic applications. Vutrisiran is a double-stranded small interfering ribonucleic acid (siRNA) that targets wild-type and mutant transthyretin (TTR) messenger RNA (mRNA). This siRNA therapeutic is indicated for the treatment of neuropathies associated with hereditary transthyretin-mediated amyloidosis (ATTR), a condition caused by mutations in the TTR gene. More than 130 TTR mutations have been identified so far, but the most common one is the replacement of valine with methionine at position 30 (Val30Met). The Val30Met variant is the most prevalent among hereditary ATTR patients with polyneuropathy, especially in Portugal, France, Sweden, and Japan. TTR mutations lead to the formation of misfolded TTR proteins, which form amyloid fibrils that deposit in different types of tissues. By targeting TTR mRNA, vutrisiran reduces the serum levels of TTR. Vutrisiran is commercially available as a conjugate of N-acetylgalactosamine (GalNAc), a residue that enables the delivery of siRNA to hepatocytes. This delivery platform gives vutrisiran high potency and metabolic stability, and allows for subcutaneous injections to take place once every three months. Another siRNA indicated for the treatment of polyneuropathy associated with hereditary ATTR is . Vutrisiran was approved by the FDA in June 2022.

Indications:

This drug is primarily indicated for: Vutrisiran is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Vutrisiran undergoes metabolic processing primarily in: As a small interfering ribonucleic acid (siRNA), vutrisiran is metabolized by endo- and exonucleases to produce short nucleotide fragments of varying sizes within the liver. _In vitro_ studies suggest that vutrisiran is not a substrate or inhibitor of cytochrome P450 enzymes. Since vutrisiran does not induce CYP enzymes or activate drug transporters, drug-drug interactions are not expected. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Vutrisiran are crucial for its therapeutic efficacy: In subjects receiving 5 to 300 mg of vutrisiran, C_max increased in a dose-proportional manner, while the AUC_last and AUC_inf increased in a slightly more than dose-proportional manner. Of the 130 TTR mutations identified so far, more than 40 of them were detected in patients of Japanese descent. The pharmacokinetic parameters of vutrisiran were comparable in both Japanese and non-Japanese healthy subjects given 25 mg subcutaneously. Japanese subjects had an AUC_0-last of 1.04 h∙µg/mL and a C_max 0.120 µg/mL. Non-Japanese subjects had an AUC_0-last of 0.854 h∙µg/mL and a C_max 0.0875 µg/mL. The average T_max of vutrisiran is 4 h, ranging from 0.17 to 12.0 h. Human bioavailability studies have not been performed; however, studies in rats have shown that N-acetylgalactosamine (GalNAc)-conjugated and unconjugated small interfering ribonucleic acids (siRNAs) given subcutaneously have 100% bioavailability. Plasma accumulation was not detected in hereditary transthyretin-mediated amyloidosis (ATTR) patients given 25 mg of vutrisiran every 3 months. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Vutrisiran is an important consideration for its dosing schedule: The median half-life of vutrisiran was 5.2 h (2.2 to 6.4 h range) in healthy subjects given a single dose of 25 mg. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Vutrisiran exhibits a strong affinity for binding with plasma proteins: Vutrisiran is 80% bound to plasma proteins. Plasma protein binding was concentration-dependent and decreased as vutrisiran concentrations increased, going from 78% at 0.5 mcg/mL to 19% at 50 mcg/mL. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Vutrisiran from the body primarily occurs through: Vutrisiran has a rapid elimination from systemic circulation. The mean renal clearance of vutrisiran goes from 4.5 to 5.7 L/hour, and the fraction of renal clearance to total clearance (CLR/) ranges from 15.5% to 27.5%, suggesting that renal excretion of vutrisiran is a minor route of elimination. At the recommended dose of 25 mg, approximately 19.4% of unchanged vutrisiran was eliminated in urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Vutrisiran is distributed throughout the body with a volume of distribution of: Based on a population pharmacokinetic model estimation, the apparent volume of distribution of vutrisiran is 10.1 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Vutrisiran is a critical factor in determining its safe and effective dosage: The apparent clearance of vutrisiran was 21.4 L/h (19.8 to 30 L/h range) in healthy subjects given a single dose of 25 mg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Vutrisiran exerts its therapeutic effects through: The reduction of serum transthyretin (TTR) achieved with vutrisiran is dose-dependent and detected within days of dosing. Healthy subjects given a single subcutaneous dose of 25 mg of vutrisiran had a maximum TTR reduction of 80%. In patients with hereditary transthyretin-mediated amyloidosis (ATTR), vutrisiran reduced mean serum TTR by 83% at a steady state. At doses of 5–300 mg, the maximum TTR reduction was detected at 50–90 days and maintained for 90 days at doses of 25 mg or higher. The reduction in serum TTR achieved with vutrisiran is similar regardless of Val30Met genotype status, weight, sex, age, or race. Vutrisiran does not have a clinically significant effect on QT prolongation. Over 9 months of treatment, vutrisiran reduced serum vitamin A levels by 62%. Supplementation of vitamin A in patients treated with vutrisiran is recommended; however, doses higher than the recommended daily allowance should not be given. Patients with ocular symptoms suggestive of vitamin A deficiency, such as night blindness, should be referred to an ophthalmologist. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Vutrisiran functions by: Vutrisiran is a double-stranded small interfering ribonucleic acid (siRNA) indicated for the treatment of polyneuropathy associated with hereditary transthyretin-mediated amyloidosis (ATTR). Hereditary ATTR is caused by mutations in the transthyretin (TTR) gene that destabilize the TTR protein. TTR proteins are primarily expressed in the liver, acting as carriers of vitamin A. TTR exists as a tetramer (four monomers or subunits), and is composed of 127 amino acids. Mutations in the TTR gene lead to the dissociation of the TTR tetramer into monomers. TTR monomers misfold, aggregate and form amyloid fibrils that deposit in peripheral and autonomic nerves, heart, and other organs. Vutrisiran targets wild-type and mutant TTR messenger RNA (mRNA) and promotes its degradation. This decreases the serum levels of TTR protein and lowers the amount of amyloid fibril deposits in patients with hereditary ATTR. Vutrisiran is commercially available as a conjugate of N-acetylgalactosamine (GalNAc), a molecule that binds to the asialoglycoprotein receptors (ASGPR) in hepatocytes. Therefore, the vutrisiran-GalNAc conjugate targets TTR mRNA in the liver. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Vutrisiran is categorized under the following therapeutic classes: Antisense Oligonucleotides, Nucleic Acids, Nucleotides, and Nucleosides, Oligonucleotides, RNA, Antisense, Small Interfering RNA, Transthyretin-directed RNA Interaction. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Vutrisiran include:

• Molecular Weight: 16345.0
• Molecular Formula: C530H715F9N171O323P43S6