Patisiran API Manufacturers

General Description:

Patisiran, identified by CAS number 1420706-45-1, is a notable compound with significant therapeutic applications. Parisiran is a first in class short interfering RNA for the treatment of patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis . It is marketed as Onpattro which is formulated as patisiran within a liposome envelope for better delivery to the liver, where transthyretin is produced. The approval for Onpattro was granted to Alnylam Pharmaceuticals, Inc. in August of 2018. Onpattro has been granted Fast Track, Priority Review and Breakthrough Therapy, and Orphan Drug designations.

Indications:

This drug is primarily indicated for: Patisirant is indicated for the treatment of hereditary transthyretin-mediated amyloidosis in adults . It is administered with pre-medication to reduce complications . These include an intravenous corticosteroid equivalent to 10 mg of dexamethasone, 500 mg of oral acetaminophen, an intravenous histamine H1 blocker equivalent to 50 mg of diphenhydramine, and an intravenous histamine H2 blocker equivalent to 50 mg of ranitidine. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Patisiran undergoes metabolic processing primarily in: Patisiran is metabolized to individual nucleotides and oligonucleotides of varying lengths by nucleases similarly to endogenous RNA. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Patisiran are crucial for its therapeutic efficacy: Patisiran follows a linear dose-proportional absorption curve . Over 95% of administered drug remains with the liposomal complex which distributes primarily to the liver. With chronic dosing at 0.3 mg/kg every 3 weeks, steady state is reached by 24 weeks. The accumulation factor of the AUC is 3.2 with chronic dosing. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Patisiran is an important consideration for its dosing schedule: Patisiran has a terminal elimination half-life of 3.2 ± 1.8 days . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Patisiran exhibits a strong affinity for binding with plasma proteins: Less than 2.1% of patisiran is bound to serum albumin and α1-acid glycoprotein . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Patisiran from the body primarily occurs through: Less than 1% is excreted through the urine. The bulk of the drug is broken down by nucleases . No dosage adjustment is required in patients with mild hepatic impairment or mild to moderate renal impairment. No data exists for patients with severe to end-stage renal impairment or moderate to severe hepatic impairment. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Patisiran is distributed throughout the body with a volume of distribution of: The steady state volume of distribution of patisiran is 0.26 ± 0.20 L/kg observed with chronic dosing at 0.3 mg/kg every 3 weeks . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Patisiran is a critical factor in determining its safe and effective dosage: The total body clearance of patisiran is 3.0 ± 2.5 mL/h/kg . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Patisiran exerts its therapeutic effects through: Transthyretin normally plays a role in the transport of vitamin A in conjunction with retinol binding protein . Mutant transthyretin of the ATTR genotype is capable of forming amyloid fibrils and creating protein deposits in a condition known as transthyretin-mediated amyloidosis. Patisiran reduces the amount of wild-type and mutant transthyretin mRNA available for translation through RNA interference . This has the effect of decreasing circulating transthyretin protein and reducing the amyloid deposits associated with transthyretin-mediated amyloidosis. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Patisiran functions by: Patisirant is a double-stranded short interfering RNA (siRNA) targeting mRNA encoding both wild-type and mutant transthyretin . Patisiran enters the cell an is processed by the Dicer enzyme. This processing involved cleaving overhanging nucleotides on the edges of the RNA. Once processed the siRNA can bind to the RNA-induced silencing complex (RISC). RISC separates the strands of the RNA sequence. One strand is released and one remains bound. The bound strand then acts as a targeting sequence for a complimentary mRNA sequence. In this case, the bound strand of patisiran binds to the complimentary transthyretin mRNA and aligns the RISC complex with it. The transthyretin mRNA is then cleaved and rendered non-functional. One targeting sequence may be used to destroy many copies of complimentary mRNA. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Patisiran is categorized under the following therapeutic classes: Antisense Elements (Genetics), Compounds used in a research, industrial, or household setting, Decreased RNA Integrity, Increased Protein Breakdown, Molecular Probes, Nervous System, Nucleic Acid Probes, Nucleic Acids, Nucleic Acids, Nucleotides, and Nucleosides, Other Miscellaneous Therapeutic Agents, RNA, Antisense, RNA, Small Untranslated, RNA, Untranslated, Small Interfering RNA, Transthyretin-directed RNA Interaction. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.