Peringatan Keamanan

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.L10202

Givosiran

DB15066

biotech approved investigational

Deskripsi

Givosiran is a small interfering RNA (siRNA) directed towards 5-aminolevulinic acid synthase, a critical enzyme in the heme biosynthesis pathway.L10202 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.L10202 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.A187991 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.

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) Both givosiran and its active metabolite, AS(N-1)3' givosiran, have an elimination half-life of 6 hours.[L10202]
Volume Distribusi The apparent central volume of distribution is 10.4 L.[L10202] Both givosiran and AS(N-1)3' givosiran distribute primarily to the liver following subcutaneous administration.[L10202]
Klirens (Clearance) The apparent clearance of givosiran is 35.1 L/hr.[L10202]

Absorpsi

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.L10202 The Tmax following subcutaneous injection is approximately 3 hours.L10202

Metabolisme

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 AUC0-24 comprises approximately 45% of the parent drug AUC at the recommended givosiran dosage.L10202 In vitro studies suggest that givosiran is not a substrate of the CYP enzyme system.L10202

Rute Eliminasi

Approximately 5-14% of the dose recovered in urine is unchanged parent drug, and 4-13% is AS(N-1)3' givosiran.L10202

Interaksi Obat

953 Data
Foscarnet The risk or severity of nephrotoxicity can be increased when Givosiran is combined with Foscarnet.
Mannitol The risk or severity of nephrotoxicity can be increased when Mannitol is combined with Givosiran.
Tenofovir disoproxil Givosiran may increase the nephrotoxic activities of Tenofovir disoproxil.
Tenofovir alafenamide Givosiran may increase the nephrotoxic activities of Tenofovir alafenamide.
Tenofovir Givosiran may increase the nephrotoxic activities of Tenofovir.
Cyclosporine The risk or severity of nephrotoxicity can be increased when Cyclosporine is combined with Givosiran.
Icosapent The risk or severity of nephrotoxicity can be increased when Icosapent is combined with Givosiran.
Cefotiam The risk or severity of nephrotoxicity can be increased when Cefotiam is combined with Givosiran.
Mesalazine The risk or severity of nephrotoxicity can be increased when Mesalazine is combined with Givosiran.
Cefmenoxime The risk or severity of nephrotoxicity can be increased when Cefmenoxime is combined with Givosiran.
Cefmetazole The risk or severity of nephrotoxicity can be increased when Cefmetazole is combined with Givosiran.
Pamidronic acid The risk or severity of nephrotoxicity can be increased when Pamidronic acid is combined with Givosiran.
Indomethacin The risk or severity of nephrotoxicity can be increased when Indomethacin is combined with Givosiran.
Cidofovir The risk or severity of nephrotoxicity can be increased when Cidofovir is combined with Givosiran.
Cefpiramide The risk or severity of nephrotoxicity can be increased when Cefpiramide is combined with Givosiran.
Ceftazidime The risk or severity of nephrotoxicity can be increased when Ceftazidime is combined with Givosiran.
Loracarbef The risk or severity of nephrotoxicity can be increased when Loracarbef is combined with Givosiran.
Cefalotin The risk or severity of nephrotoxicity can be increased when Cefalotin is combined with Givosiran.
Ketorolac The risk or severity of nephrotoxicity can be increased when Ketorolac is combined with Givosiran.
Tenoxicam The risk or severity of nephrotoxicity can be increased when Tenoxicam is combined with Givosiran.
Cefotaxime The risk or severity of nephrotoxicity can be increased when Cefotaxime is combined with Givosiran.
Tolmetin The risk or severity of nephrotoxicity can be increased when Tolmetin is combined with Givosiran.
Piroxicam The risk or severity of nephrotoxicity can be increased when Piroxicam is combined with Givosiran.
Methotrexate The risk or severity of nephrotoxicity can be increased when Methotrexate is combined with Givosiran.
Cephalexin The risk or severity of nephrotoxicity can be increased when Cephalexin is combined with Givosiran.
Fenoprofen The risk or severity of nephrotoxicity can be increased when Fenoprofen is combined with Givosiran.
Valaciclovir The risk or severity of nephrotoxicity can be increased when Valaciclovir is combined with Givosiran.
Valdecoxib The risk or severity of nephrotoxicity can be increased when Valdecoxib is combined with Givosiran.
Sulindac The risk or severity of nephrotoxicity can be increased when Sulindac is combined with Givosiran.
Bacitracin The risk or severity of nephrotoxicity can be increased when Bacitracin is combined with Givosiran.
Amphotericin B The risk or severity of nephrotoxicity can be increased when Amphotericin B is combined with Givosiran.
Cephaloglycin The risk or severity of nephrotoxicity can be increased when Cephaloglycin is combined with Givosiran.
Furosemide The risk or severity of nephrotoxicity can be increased when Furosemide is combined with Givosiran.
Flurbiprofen The risk or severity of nephrotoxicity can be increased when Flurbiprofen is combined with Givosiran.
Adefovir dipivoxil The risk or severity of nephrotoxicity can be increased when Adefovir dipivoxil is combined with Givosiran.
Etodolac The risk or severity of nephrotoxicity can be increased when Etodolac is combined with Givosiran.
Sulfasalazine The risk or severity of nephrotoxicity can be increased when Sulfasalazine is combined with Givosiran.
Phenylbutazone The risk or severity of nephrotoxicity can be increased when Phenylbutazone is combined with Givosiran.
Meloxicam The risk or severity of nephrotoxicity can be increased when Meloxicam is combined with Givosiran.
Carprofen The risk or severity of nephrotoxicity can be increased when Carprofen is combined with Givosiran.
Cefaclor The risk or severity of nephrotoxicity can be increased when Cefaclor is combined with Givosiran.
Diflunisal The risk or severity of nephrotoxicity can be increased when Diflunisal is combined with Givosiran.
Tacrolimus The risk or severity of nephrotoxicity can be increased when Tacrolimus is combined with Givosiran.
Bumetanide The risk or severity of nephrotoxicity can be increased when Bumetanide is combined with Givosiran.
Etacrynic acid The risk or severity of nephrotoxicity can be increased when Etacrynic acid is combined with Givosiran.
Ceforanide The risk or severity of nephrotoxicity can be increased when Ceforanide is combined with Givosiran.
Salicylic acid The risk or severity of nephrotoxicity can be increased when Salicylic acid is combined with Givosiran.
Meclofenamic acid The risk or severity of nephrotoxicity can be increased when Meclofenamic acid is combined with Givosiran.
Acetylsalicylic acid The risk or severity of nephrotoxicity can be increased when Acetylsalicylic acid is combined with Givosiran.
Carboplatin The risk or severity of nephrotoxicity can be increased when Carboplatin is combined with Givosiran.
Oxaprozin The risk or severity of nephrotoxicity can be increased when Oxaprozin is combined with Givosiran.
Hydrochlorothiazide The risk or severity of nephrotoxicity can be increased when Hydrochlorothiazide is combined with Givosiran.
Ketoprofen The risk or severity of nephrotoxicity can be increased when Ketoprofen is combined with Givosiran.
Balsalazide The risk or severity of nephrotoxicity can be increased when Balsalazide is combined with Givosiran.
Ibuprofen The risk or severity of nephrotoxicity can be increased when Ibuprofen is combined with Givosiran.
Cefditoren The risk or severity of nephrotoxicity can be increased when Cefditoren is combined with Givosiran.
Atazanavir The risk or severity of nephrotoxicity can be increased when Atazanavir is combined with Givosiran.
Colistimethate The risk or severity of nephrotoxicity can be increased when Colistimethate is combined with Givosiran.
Cefuroxime The risk or severity of nephrotoxicity can be increased when Cefuroxime is combined with Givosiran.
Cefapirin The risk or severity of nephrotoxicity can be increased when Cefapirin is combined with Givosiran.
Cefadroxil The risk or severity of nephrotoxicity can be increased when Cefadroxil is combined with Givosiran.
Cefprozil The risk or severity of nephrotoxicity can be increased when Cefprozil is combined with Givosiran.
Ceftriaxone The risk or severity of nephrotoxicity can be increased when Ceftriaxone is combined with Givosiran.
Olsalazine The risk or severity of nephrotoxicity can be increased when Givosiran is combined with Olsalazine.
Lumiracoxib The risk or severity of nephrotoxicity can be increased when Lumiracoxib is combined with Givosiran.
Cefamandole The risk or severity of nephrotoxicity can be increased when Cefamandole is combined with Givosiran.
Cefazolin The risk or severity of nephrotoxicity can be increased when Cefazolin is combined with Givosiran.
Cefonicid The risk or severity of nephrotoxicity can be increased when Cefonicid is combined with Givosiran.
Cefoperazone The risk or severity of nephrotoxicity can be increased when Cefoperazone is combined with Givosiran.
Cefotetan The risk or severity of nephrotoxicity can be increased when Cefotetan is combined with Givosiran.
Cefoxitin The risk or severity of nephrotoxicity can be increased when Cefoxitin is combined with Givosiran.
Ceftizoxime The risk or severity of nephrotoxicity can be increased when Ceftizoxime is combined with Givosiran.
Cefradine The risk or severity of nephrotoxicity can be increased when Cefradine is combined with Givosiran.
Magnesium salicylate The risk or severity of nephrotoxicity can be increased when Magnesium salicylate is combined with Givosiran.
Salsalate The risk or severity of nephrotoxicity can be increased when Salsalate is combined with Givosiran.
Choline magnesium trisalicylate The risk or severity of nephrotoxicity can be increased when Choline magnesium trisalicylate is combined with Givosiran.
Cefepime The risk or severity of nephrotoxicity can be increased when Cefepime is combined with Givosiran.
Cefacetrile The risk or severity of nephrotoxicity can be increased when Cefacetrile is combined with Givosiran.
Ceftibuten The risk or severity of nephrotoxicity can be increased when Ceftibuten is combined with Givosiran.
Cefpodoxime The risk or severity of nephrotoxicity can be increased when Cefpodoxime is combined with Givosiran.
Antrafenine The risk or severity of nephrotoxicity can be increased when Antrafenine is combined with Givosiran.
Phenazopyridine The risk or severity of nephrotoxicity can be increased when Phenazopyridine is combined with Givosiran.
Tiaprofenic acid The risk or severity of nephrotoxicity can be increased when Tiaprofenic acid is combined with Givosiran.
Lopinavir The risk or severity of nephrotoxicity can be increased when Lopinavir is combined with Givosiran.
Hydrolyzed Cephalothin The risk or severity of nephrotoxicity can be increased when Hydrolyzed Cephalothin is combined with Givosiran.
Cephalothin Group The risk or severity of nephrotoxicity can be increased when Cephalothin Group is combined with Givosiran.
Oxyphenbutazone The risk or severity of nephrotoxicity can be increased when Oxyphenbutazone is combined with Givosiran.
Latamoxef The risk or severity of nephrotoxicity can be increased when Latamoxef is combined with Givosiran.
Nimesulide The risk or severity of nephrotoxicity can be increased when Nimesulide is combined with Givosiran.
Benoxaprofen The risk or severity of nephrotoxicity can be increased when Benoxaprofen is combined with Givosiran.
Metamizole The risk or severity of nephrotoxicity can be increased when Metamizole is combined with Givosiran.
Zomepirac The risk or severity of nephrotoxicity can be increased when Zomepirac is combined with Givosiran.
Ceftobiprole The risk or severity of nephrotoxicity can be increased when Ceftobiprole is combined with Givosiran.
Cimicoxib The risk or severity of nephrotoxicity can be increased when Cimicoxib is combined with Givosiran.
Ceftaroline fosamil The risk or severity of nephrotoxicity can be increased when Ceftaroline fosamil is combined with Givosiran.
Lornoxicam The risk or severity of nephrotoxicity can be increased when Lornoxicam is combined with Givosiran.
Aceclofenac The risk or severity of nephrotoxicity can be increased when Aceclofenac is combined with Givosiran.
Zaltoprofen The risk or severity of nephrotoxicity can be increased when Zaltoprofen is combined with Givosiran.
Azapropazone The risk or severity of nephrotoxicity can be increased when Azapropazone is combined with Givosiran.
Parecoxib The risk or severity of nephrotoxicity can be increased when Parecoxib is combined with Givosiran.

Target Protein

ALAS1 mRNA
5-aminolevulinate synthase, non-specific, mitochondrial ALAS1

Referensi & Sumber

Synthesis reference: Brian Bettencourt, Kevin Fitzgerald, William Querbes, Robert J. Desnick, Makiko Yasuda, "Compositions and methods for inhibiting expression of the ALAS1 gene." US Patent US10119143B2, issued November, 2018.
Artikel (PubMed)
  • PMID: 26528940
    Chan A, Liebow A, Yasuda M, Gan L, Racie T, Maier M, Kuchimanchi S, Foster D, Milstein S, Charisse K, Sehgal A, Manoharan M, Meyers R, Fitzgerald K, Simon A, Desnick RJ, Querbes W: Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification. Mol Ther Nucleic Acids. 2015 Nov 3;4:e263. doi: 10.1038/mtna.2015.36.
  • PMID: 30987916
    Bonkovsky HL, Dixon N, Rudnick S: Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Mar 6. pii: S1096-7192(19)30084-8. doi: 10.1016/j.ymgme.2019.03.002.
  • PMID: 30726693
    Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM, Desnick R, Parker C, Phillips J, Bonkovsky HL, Vassiliou D, Penz C, Chan-Daniels A, He Q, Querbes W, Fitzgerald K, Kim JB, Garg P, Vaishnaw A, Simon AR, Anderson KE: Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria. N Engl J Med. 2019 Feb 7;380(6):549-558. doi: 10.1056/NEJMoa1807838.
  • PMID: 31102718
    Fontanellas A, Avila MA, Anderson KE, Deybach JC: Current and innovative emerging therapies for porphyrias with hepatic involvement. J Hepatol. 2019 Aug;71(2):422-433. doi: 10.1016/j.jhep.2019.05.003. Epub 2019 May 16.

Contoh Produk & Brand

Produk: 3 • International brands: 0
Produk
  • Givlaari
    Injection, solution • 189 mg/mL • Subcutaneous • EU • Approved
  • Givlaari
    Solution • 189 mg / mL • Subcutaneous • Canada • Approved
  • Givlaari
    Injection, solution • 189 mg/1mL • Subcutaneous • US • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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