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General Description:

Givosiran, identified by CAS number 1639325-43-1, is a notable compound with significant therapeutic applications. Givosiran is a small interfering RNA (siRNA) directed towards 5-aminolevulinic acid synthase, a critical enzyme in the heme biosynthesis pathway. It is manufactured by Alnylam Pharmaceuticals and was first approved for use in the United States in November 2019 for the treatment of adults with acute hepatic porphyria, a genetic disorder in which the overproduction of toxic heme intermediates leads to neuro-, nephro-, and gastrotoxicity. Givosiran represents an important step forward in the treatment of acute hepatic porphyria as it is the first approved pharmacotherapy for the prevention of acute attacks - previous strategies involved non-therapeutic measures (e.g. trigger avoidance), intravenous for the treatment of attacks, and liver transplantation in refractory cases. Givosiran is the second-ever FDA-approved member of the siRNA drug class (the first being ), a new class of drugs promising an important and exciting step forward in the treatment of genetic disorders.

Indications:

This drug is primarily indicated for: Givosiran is indicated for the treatment of adults with acute hepatic porphyria. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Givosiran undergoes metabolic processing primarily in: Givosiran is metabolized to shorter oligonucleotides by nuclease enzymes. Its active metabolite, AS(N-1)3' givosiran, carries equal potency to the parent drug and its AUC_0-24 comprises approximately 45% of the parent drug AUC at the recommended givosiran dosage. _In vitro_ studies suggest that givosiran is not a substrate of the CYP enzyme system. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Givosiran are crucial for its therapeutic efficacy: The mean steady-state C_max and AUC₂₄ of givosiran are 321 ng/mL and 4130 ng·h/mL, respectively, and increase proportionally over the dosing range. The T_max following subcutaneous injection is approximately 3 hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Givosiran is an important consideration for its dosing schedule: Both givosiran and its active metabolite, AS(N-1)3' givosiran, have an elimination half-life of 6 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Givosiran exhibits a strong affinity for binding with plasma proteins: Plasma protein binding is inversely proportional to givosiran concentration, ranging from 92% at 1 μg/mL to 21% at 50 μg/mL. The specific plasma protein to which givosiran is bound is unclear. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Givosiran from the body primarily occurs through: Approximately 5-14% of the dose recovered in urine is unchanged parent drug, and 4-13% is AS(N-1)3' givosiran. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Givosiran is distributed throughout the body with a volume of distribution of: The apparent central volume of distribution is 10.4 L. Both givosiran and AS(N-1)3' givosiran distribute primarily to the liver following subcutaneous administration. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Givosiran is a critical factor in determining its safe and effective dosage: The apparent clearance of givosiran is 35.1 L/hr. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Givosiran exerts its therapeutic effects through: Givosiran decreases the rate at which toxic byproducts of heme synthesis are produced in the livers of patients with acute hepatic porphyria, thus preventing their accumulation and associated neuro-, nephro-, and gastrotoxicity. As givosiran works at the transcriptional level, it has a long duration of action and can be administered subcutaneously on a monthly basis. Although givosiran appears to be relatively well-tolerated, hepatic and renal toxicity were noted during clinical trials. Patients receiving therapy with givosiran should undergo routine laboratory monitoring of liver and kidney function. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Givosiran functions by: Acute hepatic porphyrias are a class of genetic disorders involving deficiencies in the pathway responsible for heme synthesis in liver hepatocytes. The rate-limiting step in heme synthesis is the first enzyme in the pathway, 5-aminolevulinic acid synthase (ALAS1), which is controlled via a negative feedback loop by the presence of heme end-product in the liver. Deficiencies in later enzymes in the pathway result in low circulating levels of heme, which in turn stimulates the up-regulation of ALAS1. The overexpression of ALAS1, in combination with downstream enzyme deficiencies, leads to the overproduction and accumulation of toxic heme intermediates which are ultimately responsible for the neurovisceral symptoms characteristic of acute hepatic porphyrias. Givosiran is a double-stranded small interfering RNA (siRNA) directed at ALAS1 mRNA in hepatocytes. It is covalently bound to a ligand containing three N-acetylgalactosamine (GalNAc) residues that facilitate uptake into hepatocytes via asialoglycoprotein receptors (ASPGRs), which are highly expressed on the cell surface of hepatocytes and are selective for glycoproteins containing GalNAc residues. Following endocytosis into hepatocytes, the antisense strand of givosiran is loaded into an enzyme complex called the RNA-induced silencing complex (RISC), which uses the antisense strand to seek out and selectively cleave the complementary mRNA sequence (in this case found between nucleotide 918 and 937 of the ALAS1 mRNA). Cleavage of the ALAS1 mRNA results in its degradation, preventing the synthesis of the ALAS1 enzyme and ultimately leading to reduced circulating levels of neurotoxic heme intermediates. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Givosiran is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Amino Sugars, Aminolevulinate Synthase 1-Directed Small Interfering RNAs, Antisense Oligonucleotides, Carbohydrates, Galactosamine, Hepatotoxic Agents, Hexosamines, Nephrotoxic agents, Oligonucleotides, Other Miscellaneous Therapeutic Agents, Porphyrias, Hepatic, RNA, Antisense, Small Interfering RNA, Various Alimentary Tract and Metabolism Products. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Givosiran include:

• Molecular Weight: 16300.0
• Molecular Formula: C524 H694 F16 N173 O316 P43 S6