Peringatan Keamanan

There are no data on the developmental risk associated with the use of inotersen in pregnant women. Inotersen treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking inotersen. Vitamin A is essential for normal embryofetal development; however, excessive levels of Vitamin A are associated with adverse developmental effects. The effects on the fetus due to a reduction in maternal serum TTR caused by inotersen and vitamin A supplementation are unknown.L49711

In animal studies, subcutaneous administration of inotersen to pregnant rabbits resulted in premature delivery and reduced fetal body weight at the highest dose tested, which was associated with maternal toxicity. No adverse developmental effects were observed when inotersen or a pharmacologically active surrogate was administered to pregnant mice.L49711

In a 26-week carcinogenicity study in transgenic (TgRasH2) mice, weekly subcutaneous administration of inotersen (0, 10, 30, or 80 mg/kg) or a rodent-specific (pharmacologically active) surrogate (30 mg/kg) did not result in an increase in tumors.L49711

In a 94-week carcinogenicity study in rats, weekly subcutaneous administration of inotersen (0, 0.5, 2, or 6 mg/kg) resulted in an increase in tumors at or near the injection site in males at all but the lowest dose (0.5 mg/kg) tested. Subcutaneous malignant pleomorphic fibrosarcoma was increased at the mid and high doses and combined subcutaneous malignant pleomorphic fibrosarcoma and monomorphic fibrosarcoma were increased at the high dose. These tumors are considered a response to chronic tissue irritation and inflammation caused by repeated subcutaneous injection.L49711

Inotersen was negative for genotoxicity in in vitro (bacterial mutagenicity, chromosomal aberration in Chinese hamster lung) and in vivo (mouse bone marrow micronucleus) assays.L49711

Subcutaneous administration of inotersen (0, 3, 15, or 25 mg/kg) or a rodent-specific surrogate (15 mg/kg) to male and female mice every other day prior to and during mating and continuing in females throughout the period of organogenesis produced no adverse effects on fertility.L49711

Inotersen

DB14713

biotech approved investigational

Deskripsi

Inotersen is a transthyretin-directed antisense oligonucleotide for the treatment of the polyneuropathy caused by hereditary transthyretin-mediated amyloidosis in adults. It was FDA approved in October 2018.L11761 Inotersen has been shown to improve the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis A39493.

Hereditary transthyretin amyloidosis is caused by single-nucleotide variants in the gene encoding transthyretin (TTR), which lead to transthyretin misfolding and the deposition of amyloid substance systemically. Progressive amyloid accumulation may lead to multiorgan dysfunction and death A39493.

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 terminal elimination half-life (mean and 90% confidence interval) for inotersen is 32.3 (29.4, 35.5) days.[L49711]
Volume Distribusi Based on animal studies (mouse, rat, and monkey), inotersen rapidly distributes broadly to tissues, with the highest concentrations observed in the kidney and liver. Inotersen does not cross the blood-brain barrier. The apparent volume of distribution of inotersen at steady-state (mean and 90% confidence interval) is 293 (268, 320) L in patients with hATTR.[L49711]
Klirens (Clearance) Inotersen is mainly cleared through metabolism, and the total body clearance (mean and 90% confidence interval) is 3.18 (3.08, 3.29) L/h.[L49711]

Absorpsi

Following subcutaneous administration, systemic exposure to inotersen increased in a dose-proportional manner over the range of 150-400 mg of inotersen sodium salt. At the recommended inotersen dosing regimen of 284 mg every week, steady-state is reached after approximately 3 months. The estimated geometric mean (90% confidence interval) steady-state peak concentrations (Cmax), trough concentrations (Ctrough), and area under the curve (AUC?) were 6.39 (5.65, 7.20) µg/mL, 0.034 (0.031, 0.038) µg/mL, and 90 (82.4, 97.4) µg·h/mL, respectively. Plasma Cmax and AUC do not exhibit accumulation at a steady state.L49711 Following subcutaneous administration, inotersen is absorbed rapidly into the systemic circulation in a dose-dependent fashion, with the median time to maximum plasma concentrations (Cmax) of 2 to 4 hours.L49711

Metabolisme

Inotersen is metabolized by nucleases to nucleotides of various lengths.L49711

Rute Eliminasi

Less than 1% of the administered dose of inotersen is excreted unchanged into urine within 24 hours.L49711

Interaksi Makanan

1 Data
  • 1. Administer vitamin A supplementation. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking inotersen.

Interaksi Obat

1102 Data
Foscarnet The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Foscarnet.
Mannitol The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Mannitol.
Tenofovir disoproxil The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Tenofovir disoproxil.
Tenofovir alafenamide The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Tenofovir alafenamide.
Tenofovir The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Tenofovir.
Cyclosporine The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cyclosporine.
Icosapent The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Icosapent.
Cefotiam The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefotiam.
Mesalazine The risk or severity of nephrotoxicity can be increased when Mesalazine is combined with Inotersen.
Cefmenoxime The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefmenoxime.
Cefmetazole The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefmetazole.
Indomethacin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Indomethacin.
Triamterene The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Triamterene.
Cefpiramide The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefpiramide.
Loracarbef The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Loracarbef.
Cefalotin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefalotin.
Nabumetone The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Nabumetone.
Ketorolac The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Ketorolac.
Tenoxicam The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Tenoxicam.
Celecoxib The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Celecoxib.
Cefotaxime The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefotaxime.
Tolmetin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Tolmetin.
Rofecoxib The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Rofecoxib.
Fenoprofen The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Fenoprofen.
Valdecoxib The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Valdecoxib.
Diclofenac The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Diclofenac.
Sulindac The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Sulindac.
Bacitracin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Bacitracin.
Amphotericin B The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Amphotericin B.
Cephaloglycin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cephaloglycin.
Adefovir dipivoxil The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Adefovir dipivoxil.
Mefenamic acid The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Mefenamic acid.
Naproxen The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Naproxen.
Sulfasalazine The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Sulfasalazine.
Phenylbutazone The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Phenylbutazone.
Meloxicam The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Meloxicam.
Carprofen The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Carprofen.
Tacrolimus The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Tacrolimus.
Etacrynic acid The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Etacrynic acid.
Ceforanide The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Ceforanide.
Salicylic acid The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Salicylic acid.
Acetylsalicylic acid The risk or severity of thrombocytopenia can be increased when Inotersen is combined with Acetylsalicylic acid.
Hydrochlorothiazide The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Hydrochlorothiazide.
Balsalazide The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Balsalazide.
Cefditoren The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefditoren.
Atazanavir The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Atazanavir.
Colistimethate The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Colistimethate.
Cefuroxime The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefuroxime.
Cefapirin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefapirin.
Cefprozil The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefprozil.
Olsalazine The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Olsalazine.
Lumiracoxib The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Lumiracoxib.
Cefamandole The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefamandole.
Cefazolin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefazolin.
Cefonicid The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefonicid.
Cefoperazone The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefoperazone.
Cefoxitin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefoxitin.
Ceftizoxime The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Ceftizoxime.
Magnesium salicylate The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Magnesium salicylate.
Salsalate The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Salsalate.
Choline magnesium trisalicylate The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Choline magnesium trisalicylate.
Cefepime The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefepime.
Cefacetrile The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefacetrile.
Cefpodoxime The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefpodoxime.
Antrafenine The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Antrafenine.
Aminophenazone The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Aminophenazone.
Antipyrine The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Antipyrine.
Tiaprofenic acid The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Tiaprofenic acid.
Etoricoxib The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Etoricoxib.
Hydrolyzed Cephalothin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Hydrolyzed Cephalothin.
Cephalothin Group The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cephalothin Group.
Oxyphenbutazone The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Oxyphenbutazone.
Latamoxef The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Latamoxef.
Nimesulide The risk or severity of thrombocytopenia can be increased when Inotersen is combined with Nimesulide.
Benoxaprofen The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Benoxaprofen.
Metamizole The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Metamizole.
Zomepirac The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Zomepirac.
Ceftobiprole The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Ceftobiprole.
Cimicoxib The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cimicoxib.
Ceftaroline fosamil The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Ceftaroline fosamil.
Lornoxicam The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Lornoxicam.
Zaltoprofen The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Zaltoprofen.
Azapropazone The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Azapropazone.
Parecoxib The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Parecoxib.
Salicylamide The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Salicylamide.
Kebuzone The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Kebuzone.
Isoxicam The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Isoxicam.
Indoprofen The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Indoprofen.
Ibuproxam The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Ibuproxam.
Floctafenine The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Floctafenine.
Fenbufen The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Fenbufen.
Etofenamate The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Etofenamate.
Epirizole The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Epirizole.
Cefaloridine The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefaloridine.
Cefminox The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Cefminox.
Dexibuprofen The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Dexibuprofen.
Droxicam The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Droxicam.
Tolfenamic acid The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Tolfenamic acid.
Firocoxib The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Firocoxib.
Clonixin The risk or severity of nephrotoxicity can be increased when Inotersen is combined with Clonixin.

Target Protein

Transthyretin TTR
Transthyretin mRNA

Referensi & Sumber

Artikel (PubMed)
  • PMID: 29972757
    Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH 3rd, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceicao I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW, Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T: Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):22-31. doi: 10.1056/NEJMoa1716793.
  • PMID: 29240946
    Shen X, Corey DR: Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res. 2018 Feb 28;46(4):1584-1600. doi: 10.1093/nar/gkx1239.
  • PMID: 29185862
    Crooke ST, Baker BF, Pham NC, Hughes SG, Kwoh TJ, Cai D, Tsimikas S, Geary RS, Bhanot S: The Effects of 2'-O-Methoxyethyl Oligonucleotides on Renal Function in Humans. Nucleic Acid Ther. 2018 Feb;28(1):10-22. doi: 10.1089/nat.2017.0693. Epub 2017 Nov 29.
Attachment

Contoh Produk & Brand

Produk: 4 • International brands: 0
Produk
  • Tegsedi
    Solution • 284 mg / 1.5 mL • Subcutaneous • Canada • Approved
  • Tegsedi
    Injection, solution • 284 mg • Subcutaneous • EU • Approved
  • Tegsedi
    Injection, solution • 284 mg • Subcutaneous • EU • Approved
  • Tegsedi
    Injection, solution • 284 mg/1.5mL • Subcutaneous • US • Approved

Sekuens Gen/Protein (FASTA)

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