Peringatan Keamanan

Toxicity information regarding vutrisiran is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as atrioventricular (AV) heart block and complete AV block.L42065 Symptomatic and supportive measures are recommended. In vitro assays of bacterial mutagenicity and chromosomal aberration in human blood peripheral lymphocytes, as well as in vivo assays of bone marrow micronucleus in rats, have shown that vutrisiran is non-mutagenic. In male and female rats, the subcutaneous administration of 0, 15, 30, or 70 mg/kg/week of vutrisiran during mating did not have an effect on reproductive performance. Similar results were obtained in female rats followed through gestation day 6.L42065 Carcinogenicity studies of vutrisiran have not been performed.L42065

Vutrisiran

DB16699

biotech approved investigational

Deskripsi

Vutrisiran is a double-stranded small interfering ribonucleic acid (siRNA) that targets wild-type and mutant transthyretin (TTR) messenger RNA (mRNA).L42065 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.A249010 More than 130 TTR mutations have been identified so far,A249015 but the most common one is the replacement of valine with methionine at position 30 (Val30Met).A249010 The Val30Met variant is the most prevalent among hereditary ATTR patients with polyneuropathy, especially in Portugal, France, Sweden, and Japan.A249010

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.L34490,L42065 Vutrisiran is commercially available as a conjugate of N-acetylgalactosamine (GalNAc), a residue that enables the delivery of siRNA to hepatocytes.A249025,L42065 This delivery platform gives vutrisiran high potency and metabolic stability, and allows for subcutaneous injections to take place once every three months.L42085 Another siRNA indicated for the treatment of polyneuropathy associated with hereditary ATTR is patisiran.A249010 Vutrisiran was approved by the FDA in June 2022.

Struktur Molekul 2D

Struktur tidak tersedia

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) 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.[L42065]
Volume Distribusi Based on a population pharmacokinetic model estimation, the apparent volume of distribution of vutrisiran is 10.1 L.[L42065]
Klirens (Clearance) 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.[L42065]

Absorpsi

In subjects receiving 5 to 300 mg of vutrisiran, Cmax increased in a dose-proportional manner, while the AUClast and AUCinf increased in a slightly more than dose-proportional manner.L42065 Of the 130 TTR mutations identified so far, more than 40 of them were detected in patients of Japanese descent.A249015 The pharmacokinetic parameters of vutrisiran were comparable in both Japanese and non-Japanese healthy subjects given 25 mg subcutaneously. Japanese subjects had an AUC0-last of 1.04 h?µg/mL and a Cmax 0.120 µg/mL. Non-Japanese subjects had an AUC0-last of 0.854 h?µg/mL and a Cmax 0.0875 µg/mL.A249020 The average Tmax of vutrisiran is 4 h, ranging from 0.17 to 12.0 h.L42065 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.A249020 Plasma accumulation was not detected in hereditary transthyretin-mediated amyloidosis (ATTR) patients given 25 mg of vutrisiran every 3 months.L42065

Metabolisme

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.L42065 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.L42065

Rute Eliminasi

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/CL/F) ranges from 15.5% to 27.5%, suggesting that renal excretion of vutrisiran is a minor route of elimination.A249020 At the recommended dose of 25 mg, approximately 19.4% of unchanged vutrisiran was eliminated in urine.L42065

Interaksi Obat

0 Data
Tidak ada data.

Target Protein

Transthyretin mRNA

Referensi & Sumber

Synthesis reference: Zimmermann, T., et al. (2017). Transthyretin (TTR) iRNA compositions and methods of use thereof for treating or preventing TTR-associated diseases (WO 2017/023660 A1). World Intellectual Property Organization. https://patentimages.storage.googleapis.com/13/42/80/768cd7debf24f6/WO2017023660A1.pdf
Artikel (PubMed)
  • PMID: 26663427
    Conceicao I, Gonzalez-Duarte A, Obici L, Schmidt HH, Simoneau D, Ong ML, Amass L: "Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016 Mar;21(1):5-9. doi: 10.1111/jns.12153.
  • PMID: 26611723
    Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB: Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015;47(8):625-38. doi: 10.3109/07853890.2015.1068949. Epub 2015 Nov 27.
  • PMID: 29343286
    Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y: Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018 Jan 17;13(1):6. doi: 10.1186/s13023-017-0726-x.
  • PMID: 32599652
    Habtemariam BA, Karsten V, Attarwala H, Goel V, Melch M, Clausen VA, Garg P, Vaishnaw AK, Sweetser MT, Robbie GJ, Vest J: Single-Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N-acetylgalactosamine-Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects. Clin Pharmacol Ther. 2021 Feb;109(2):372-382. doi: 10.1002/cpt.1974. Epub 2020 Aug 13.
  • PMID: 29792572
    Springer AD, Dowdy SF: GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics. Nucleic Acid Ther. 2018 Jun;28(3):109-118. doi: 10.1089/nat.2018.0736. Epub 2018 May 24.

Contoh Produk & Brand

Produk: 3 • International brands: 1
Produk
  • Amvuttra
    Injection • 25 mg/0.5mL • Subcutaneous • US • Approved
  • Amvuttra
    Injection, solution • 25 mg • Subcutaneous • EU • Approved
  • Amvuttra
    Solution • 25 mg / 0.5 mL • Subcutaneous • Canada • Approved
International Brands
  • Amvuttra — Alnylam Pharmaceuticals, Inc.

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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