Indications
Givosiran is specifically indicated for the treatment of adults diagnosed with acute hepatic porphyria. This condition is a group of rare genetic disorders characterized by debilitating neurovisceral attacks and significant liver complications.
Pharmacodynamics
The mechanism of action of givosiran involves the reduction of toxic byproducts associated with heme synthesis within the liver. By decreasing the rate of production of these toxic compounds, givosiran helps in preventing their accumulation, which can lead to neurotoxicity, nephrotoxicity, and gastrointestinal toxicity in patients with acute hepatic porphyria. Given its action at the transcriptional level, givosiran exhibits a prolonged duration of action, allowing for a subcutaneous monthly administration schedule. While generally well-tolerated, clinical trials have reported instances of hepatic and renal toxicity. Therefore, it is recommended that patients undergoing treatment with givosiran receive routine laboratory monitoring to assess liver and kidney function.
Absorption
Upon subcutaneous administration, givosiran achieves a mean steady-state maximum concentration (Cmax) of 321 ng/mL and an area under the concentration-time curve over 24 hours (AUC24) of 4130 ng·h/mL. These pharmacokinetic parameters increase proportionally within the dosing range. The time to reach maximum concentration (Tmax) is approximately 3 hours after injection.
Metabolism
Givosiran undergoes metabolism through nuclease enzymes, resulting in the formation of shorter oligonucleotide metabolites. One of these, AS(N-1)3' givosiran, retains equivalent potency to the parent compound, with its exposure (AUC0-24) accounting for about 45% of that of the parent drug at the recommended dosage. In vitro studies indicate that givosiran is not metabolized via the cytochrome P450 (CYP) enzyme system.
Mechanism of Action
Givosiran functions as a therapeutic agent for acute hepatic porphyrias by targeting the mRNA of 5-aminolevulinic acid synthase 1 (ALAS1) within liver hepatocytes. Acute hepatic porphyrias are genetic disorders characterized by disruptions in the heme synthesis pathway due to enzyme deficiencies. Normally, the heme synthesis enzyme ALAS1 is regulated through a negative feedback loop by the heme end-product. However, enzyme deficiencies later in the pathway lead to diminished heme levels, prompting the up-regulation of ALAS1 and causing an accumulation of toxic heme intermediates, which result in the neurovisceral symptoms associated with these disorders. Givosiran, an siRNA molecule, is chemically linked to a ligand with three N-acetylgalactosamine (GalNAc) residues, enhancing its uptake into hepatocytes via asialoglycoprotein receptors, which are highly expressed on their surfaces. Once internalized, givosiran's antisense strand is incorporated into the RNA-induced silencing complex (RISC). This complex uses the antisense strand to specifically identify and degrade the ALAS1 mRNA at a sequence located between nucleotides 918 and 937, thereby curbing ALAS1 enzyme production. This process effectively reduces the levels of neurotoxic heme intermediates in the circulation.
