Peringatan Keamanan

Based on findings from animal studies and its mechanism of action, nirogacestat can cause fetal harm or loss of pregnancy when administered to a pregnant woman. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and embryo-fetal death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily. There are no available data on the use of nirogacestat in pregnant women. Advise pregnant women of the potential risk to a fetus.L48857

Due to the high level of protein binding, nirogacestat is not expected to be dialyzable.L48857

In a 6-month carcinogenicity study, transgenic rasH2 mice received up to 100 mg/kg/day of oral nirogacestat, resulting in mean exposure levels (AUC) less than those in humans at the recommended dose of 150 mg twice daily. No statistically significant neoplastic findings occurred. The carcinogenic potential of nirogacestat in rats has not been assessed.L48857

Nirogacestat was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro chromosome aberration assay in human lymphocytes or in vivo rat bone marrow micronucleus study.L48857

Nirogacestat resulted in reduced fertility when administered to male and female rats at doses ? 5 mg/kg/day (approximately 0.16 times the recommended dose of 150 mg twice daily based on body surface area (BSA), and a lack of fertility when administered to male and female rats at doses ? 40 mg/kg/day (approximately 1.3 times the recommended dose of 150 mg twice daily based on BSA). Adverse findings in rats included ovarian atrophy, reduced testes weights, and decreased sperm concentration and motility.L48857

Nirogacestat

DB12005

small molecule approved investigational

Deskripsi

Nirogacestat is a small-molecule gamma-secretase inhibitor that was investigated as a potential treatment for desmoid tumors. Desmoid tumors are typically characterized by aberrant activation in Notch signaling.A262556 Interaction between the notch receptors and their ligands activates proteolytic cleavage by gamma-secretase; therefore, the inhibition of gamma-secretase can potentially inhibit Notch signaling and thus impede the growth of desmoid tumors.A262561

Nirogacestat was approved under the brand name OGSIVEO on November 27, 2023, by the FDA for the treatment of adult patients with progressing desmoid tumors who require systemic treatment. It was previously granted breakthrough therapy, fast track, and orphan drug designations for the treatment of desmoid tumors, and the final approval was based on positive results obtained in the Phase 3 DeFi trial, where a confirmed objective response rate was observed to be 41% compared to 8% with the placebo.L49036

Struktur Molekul 2D

Berat 489.656
Wujud solid

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 (%CV)] of nirogacestat is 23 (37) hr .[L48857]
Volume Distribusi The apparent volume of distribution [Mean (%CV)] of nirogacestat is 1430 (65) L.[L48857]
Klirens (Clearance) The apparent systemic clearance [Mean (%CV)] of nirogacestat is 45 (58) L/hr.[L48857]

Absorpsi

The following pharmacokinetics parameters in patients with desmoid tumors were calculated as follows: Cmax (508 (62) ng/mL), AUC0-tau (u 3370 (58) ng·h/mL), time to steady state (6 days), and Tmax (1.5 (0.5, 6.5) hours).L48857

Metabolisme

Nirogacestat is expected to be metabolized primarily through the N-dealkylation via CYP3A4 (85%), with the involvement of CYP3A4, CYP2C19, CYP2C9, and CYP2D6 in a minor secondary pathway.L48857

Rute Eliminasi

Nirogacestat is excreted mostly in feces (38%) and urine 17%, with less than 1% of the unchanged drug remains in the urine. It can also be eliminated through expired air (9.7%).L48857

Interaksi Makanan

3 Data
  • 1. Avoid grapefruit products. Nirogacestat is a CYP3A substrate and grapefruit is a known CYP3A inhibitors.
  • 2. Take separate from antacids. take nirogacestat 2 hours before or 2 hours after taking the antacid.
  • 3. Take with or without food.

Interaksi Obat

862 Data
Nelfinavir The serum concentration of Nirogacestat can be increased when it is combined with Nelfinavir.
Indinavir The serum concentration of Nirogacestat can be increased when it is combined with Indinavir.
Terfenadine The serum concentration of Nirogacestat can be increased when it is combined with Terfenadine.
Ritonavir The serum concentration of Nirogacestat can be increased when it is combined with Ritonavir.
Voriconazole The serum concentration of Nirogacestat can be increased when it is combined with Voriconazole.
Efavirenz The serum concentration of Nirogacestat can be increased when it is combined with Efavirenz.
Ergotamine The serum concentration of Nirogacestat can be increased when it is combined with Ergotamine.
Amprenavir The serum concentration of Nirogacestat can be increased when it is combined with Amprenavir.
Delavirdine The serum concentration of Nirogacestat can be increased when it is combined with Delavirdine.
Methimazole The serum concentration of Nirogacestat can be increased when it is combined with Methimazole.
Conivaptan The serum concentration of Nirogacestat can be increased when it is combined with Conivaptan.
Tipranavir The serum concentration of Nirogacestat can be increased when it is combined with Tipranavir.
Telithromycin The serum concentration of Nirogacestat can be increased when it is combined with Telithromycin.
Ketoconazole The serum concentration of Nirogacestat can be increased when it is combined with Ketoconazole.
Atazanavir The serum concentration of Nirogacestat can be increased when it is combined with Atazanavir.
Amiodarone The serum concentration of Nirogacestat can be increased when it is combined with Amiodarone.
Econazole The serum concentration of Nirogacestat can be increased when it is combined with Econazole.
Nefazodone The serum concentration of Nirogacestat can be increased when it is combined with Nefazodone.
Itraconazole The serum concentration of Nirogacestat can be increased when it is combined with Itraconazole.
Clarithromycin The serum concentration of Nirogacestat can be increased when it is combined with Clarithromycin.
Saquinavir The serum concentration of Nirogacestat can be increased when it is combined with Saquinavir.
Posaconazole The serum concentration of Nirogacestat can be increased when it is combined with Posaconazole.
Darunavir The serum concentration of Nirogacestat can be increased when it is combined with Darunavir.
Danazol The serum concentration of Nirogacestat can be increased when it is combined with Danazol.
Lopinavir The serum concentration of Nirogacestat can be increased when it is combined with Lopinavir.
Ditiocarb The serum concentration of Nirogacestat can be increased when it is combined with Ditiocarb.
Nilotinib The serum concentration of Nirogacestat can be increased when it is combined with Nilotinib.
Telaprevir The serum concentration of Nirogacestat can be increased when it is combined with Telaprevir.
Levoketoconazole The serum concentration of Nirogacestat can be increased when it is combined with Levoketoconazole.
Lonafarnib The serum concentration of Nirogacestat can be increased when it is combined with Lonafarnib.
Midostaurin The serum concentration of Nirogacestat can be increased when it is combined with Midostaurin.
Boceprevir The serum concentration of Nirogacestat can be increased when it is combined with Boceprevir.
Cobicistat The serum concentration of Nirogacestat can be increased when it is combined with Cobicistat.
Elvitegravir The serum concentration of Nirogacestat can be increased when it is combined with Elvitegravir.
Stiripentol The metabolism of Nirogacestat can be decreased when combined with Stiripentol.
Curcumin The serum concentration of Nirogacestat can be increased when it is combined with Curcumin.
Ribociclib The serum concentration of Nirogacestat can be increased when it is combined with Ribociclib.
Danoprevir The serum concentration of Nirogacestat can be increased when it is combined with Danoprevir.
Troleandomycin The serum concentration of Nirogacestat can be increased when it is combined with Troleandomycin.
Cyclosporine The serum concentration of Nirogacestat can be increased when it is combined with Cyclosporine.
Fluvoxamine The serum concentration of Nirogacestat can be increased when it is combined with Fluvoxamine.
Fluconazole The serum concentration of Nirogacestat can be increased when it is combined with Fluconazole.
Erythromycin The serum concentration of Nirogacestat can be increased when it is combined with Erythromycin.
Ziprasidone The serum concentration of Nirogacestat can be increased when it is combined with Ziprasidone.
Isradipine The serum concentration of Nirogacestat can be increased when it is combined with Isradipine.
Diltiazem The serum concentration of Nirogacestat can be increased when it is combined with Diltiazem.
Clozapine The serum concentration of Nirogacestat can be increased when it is combined with Clozapine.
Haloperidol The serum concentration of Haloperidol can be increased when it is combined with Nirogacestat.
Ciprofloxacin The serum concentration of Nirogacestat can be increased when it is combined with Ciprofloxacin.
Nicardipine The serum concentration of Nirogacestat can be increased when it is combined with Nicardipine.
Verapamil The serum concentration of Nirogacestat can be increased when it is combined with Verapamil.
Aprepitant The serum concentration of Nirogacestat can be increased when it is combined with Aprepitant.
Isoniazid The serum concentration of Nirogacestat can be increased when it is combined with Isoniazid.
Tioconazole The serum concentration of Nirogacestat can be increased when it is combined with Tioconazole.
Primaquine The serum concentration of Nirogacestat can be increased when it is combined with Primaquine.
Miconazole The serum concentration of Nirogacestat can be increased when it is combined with Miconazole.
Fusidic acid The serum concentration of Nirogacestat can be increased when it is combined with Fusidic acid.
Zimelidine The serum concentration of Nirogacestat can be increased when it is combined with Zimelidine.
Dronedarone The serum concentration of Nirogacestat can be increased when it is combined with Dronedarone.
Milnacipran The serum concentration of Nirogacestat can be increased when it is combined with Milnacipran.
Simeprevir The serum concentration of Nirogacestat can be increased when it is combined with Simeprevir.
Isavuconazonium The serum concentration of Nirogacestat can be increased when it is combined with Isavuconazonium.
Desvenlafaxine The serum concentration of Nirogacestat can be increased when it is combined with Desvenlafaxine.
Nilvadipine The serum concentration of Nirogacestat can be increased when it is combined with Nilvadipine.
Seproxetine The serum concentration of Nirogacestat can be increased when it is combined with Seproxetine.
Crizotinib The serum concentration of Crizotinib can be increased when it is combined with Nirogacestat.
Linagliptin The serum concentration of Nirogacestat can be increased when it is combined with Linagliptin.
Luliconazole The serum concentration of Nirogacestat can be increased when it is combined with Luliconazole.
Indalpine The serum concentration of Nirogacestat can be increased when it is combined with Indalpine.
Netupitant The serum concentration of Nirogacestat can be increased when it is combined with Netupitant.
Barnidipine The serum concentration of Nirogacestat can be increased when it is combined with Barnidipine.
Benidipine The serum concentration of Nirogacestat can be increased when it is combined with Benidipine.
Venetoclax The serum concentration of Nirogacestat can be increased when it is combined with Venetoclax.
Isavuconazole The serum concentration of Nirogacestat can be increased when it is combined with Isavuconazole.
Fosnetupitant The serum concentration of Nirogacestat can be increased when it is combined with Fosnetupitant.
Berotralstat The serum concentration of Berotralstat can be increased when it is combined with Nirogacestat.
Phenytoin The serum concentration of Nirogacestat can be decreased when it is combined with Phenytoin.
Pentobarbital The serum concentration of Nirogacestat can be decreased when it is combined with Pentobarbital.
Carbamazepine The serum concentration of Nirogacestat can be decreased when it is combined with Carbamazepine.
Mitotane The serum concentration of Nirogacestat can be decreased when it is combined with Mitotane.
Primidone The serum concentration of Nirogacestat can be decreased when it is combined with Primidone.
Rimexolone The serum concentration of Nirogacestat can be decreased when it is combined with Rimexolone.
Rifampin The serum concentration of Nirogacestat can be decreased when it is combined with Rifampicin.
Phenobarbital The serum concentration of Nirogacestat can be decreased when it is combined with Phenobarbital.
Rifapentine The serum concentration of Nirogacestat can be decreased when it is combined with Rifapentine.
Dexamethasone The serum concentration of Nirogacestat can be decreased when it is combined with Dexamethasone.
Fosphenytoin The serum concentration of Nirogacestat can be decreased when it is combined with Fosphenytoin.
St. John's Wort The serum concentration of Nirogacestat can be decreased when it is combined with St. John's Wort.
Enzalutamide The serum concentration of Nirogacestat can be decreased when it is combined with Enzalutamide.
Lumacaftor The serum concentration of Nirogacestat can be decreased when it is combined with Lumacaftor.
Apalutamide The serum concentration of Nirogacestat can be increased when it is combined with Apalutamide.
Bexarotene The serum concentration of Nirogacestat can be decreased when it is combined with Bexarotene.
Bosentan The serum concentration of Nirogacestat can be decreased when it is combined with Bosentan.
Nafcillin The serum concentration of Nirogacestat can be decreased when it is combined with Nafcillin.
Modafinil The serum concentration of Nirogacestat can be decreased when it is combined with Modafinil.
Etravirine The serum concentration of Nirogacestat can be decreased when it is combined with Etravirine.
Avasimibe The serum concentration of Nirogacestat can be decreased when it is combined with Avasimibe.
Echinacea The serum concentration of Nirogacestat can be decreased when it is combined with Echinacea.
Dexamethasone acetate The serum concentration of Nirogacestat can be decreased when it is combined with Dexamethasone acetate.
Pantoprazole The serum concentration of Nirogacestat can be decreased when it is combined with Pantoprazole.

Target Protein

Gamma-secretase subunit APH-1B APH1B
Nicastrin NCSTN
Presenilin-1 PSEN1
Gamma-secretase subunit PEN-2 PSENEN
Gamma-secretase subunit APH-1A APH1A
Presenilin-2 PSEN2

Referensi & Sumber

Artikel (PubMed)
  • PMID: 36884323
    Gounder M, Ratan R, Alcindor T, Schoffski P, van der Graaf WT, Wilky BA, Riedel RF, Lim A, Smith LM, Moody S, Attia S, Chawla S, D'Amato G, Federman N, Merriam P, Van Tine BA, Vincenzi B, Benson C, Bui NQ, Chugh R, Tinoco G, Charlson J, Dileo P, Hartner L, Lapeire L, Mazzeo F, Palmerini E, Reichardt P, Stacchiotti S, Bailey HH, Burgess MA, Cote GM, Davis LE, Deshpande H, Gelderblom H, Grignani G, Loggers E, Philip T, Pressey JG, Kummar S, Kasper B: Nirogacestat, a gamma-Secretase Inhibitor for Desmoid Tumors. N Engl J Med. 2023 Mar 9;388(10):898-912. doi: 10.1056/NEJMoa2210140.
  • PMID: 17332312
    Shih IeM, Wang TL: Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 2007 Mar 1;67(5):1879-82. doi: 10.1158/0008-5472.CAN-06-3958.

Contoh Produk & Brand

Produk: 3 • International brands: 0
Produk
  • Ogsiveo
    Tablet, film coated • 50 mg/1 • Oral • US • Approved
  • Ogsiveo
    Tablet, film coated • 100 mg/1 • Oral • US • Approved
  • Ogsiveo
    Tablet, film coated • 150 mg/1 • Oral • US • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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