Givosiran
Givosiran Uses, Dosage, Side Effects, Food Interaction and all others data.
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 hemin 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 patisiran), a new class of drugs promising an important and exciting step forward in the treatment of genetic disorders.
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.
| Trade Name | Givosiran |
| Availability | Prescription only |
| Generic | Givosiran |
| Givosiran Other Names | Givosiran |
| Related Drugs | chlorpromazine, Thorazine, Givlaari, Panhematin, hemin |
| Weight | 189mg/ml, |
| Type | Subcutaneous Solution, Subcutaneous |
| Protein binding | 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. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Givosiran is a 5-aminolevulinic acid synthase-directed small interfering RNA (siRNA) used in the prophylaxis of acute hepatic porphyria.
Givosiran is indicated for the treatment of adults with acute hepatic porphyria.
Givosiran is also used to associated treatment for these conditions: Acute Hepatic Porphyria (AHP)
How Givosiran works
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.
Toxicity
Little information is currently available regarding the toxicity of givosiran. Weekly subcutaneous dosing of up to 30 mg/kg in both female and male rats resulted in no apparent effects on fertility or reproductive function.
Food Interaction
No interactions found.Givosiran Disease Interaction
Volume of Distribution
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.
Elimination Route
The mean steady-state Cmax and AUC24 of givosiran are 321 ng/mL and 4130 ng·h/mL, respectively, and increase proportionally over the dosing range. The Tmax following subcutaneous injection is approximately 3 hours.
Half Life
Both givosiran and its active metabolite, AS(N-1)3' givosiran, have an elimination half-life of 6 hours.
Clearance
The apparent clearance of givosiran is 35.1 L/hr.
Elimination Route
Approximately 5-14% of the dose recovered in urine is unchanged parent drug, and 4-13% is AS(N-1)3' givosiran.
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