Peringatan Keamanan

Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of glasdegib in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. Glasdegib is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with glasdegib. Report pregnancy exposures to Pfizer at 1-800-438-1985.L45728

In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of glasdegib during organogenesis at maternal exposures that were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus.L45728

Carcinogenicity studies have not been performed with glasdegib. Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay.L45728

Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ?50 mg/kg/day and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6 times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose.

There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage, the adverse reactions that were dose-limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness.L45728

Glasdegib

DB11978

small molecule approved investigational

Deskripsi

Glasdegib, also known as PF-04449913, is a small-molecule hedgehog signaling inhibitor selected under the group of benzimidazoles. In early research, benzimidazoles attracted large interest as they represented a class of inhibitors with low molecular weight, potent inhibitory activity, and lacking unstable functionality.A40310 The great lipophilicity of this group of compounds brought interest to further modification. This analysis concluded that the presence of p-cyano ureas presented good physicochemical and pharmacokinetic properties from which glasdegib was developed.A40310

Glasdegib was developed by Pfizer Inc and approved on November 21, 2018 by the FDA for the treatment of Acute Myeloid Leukemia (AML).L11935 Glasdegib targets cancerous cells by inhibiting the sonic hedgehog receptor smoothened (SMO), a transmembrane protein involved in the Hedgehog (Hh) signaling cascade.A258493 Aberrant of Hh signaling is one of the main pathophysiologies of AML, with observed overexpression or constitutive activation of SMO.A258498,A258503 Although the efficacy of glasdegib monotherapy is limited, the landmark Phase 2 Bright AML 1003 trial showed a superior overall survival and complete response when glasdegib is combined with low dose cytarabine. Currently, the current gold standard of AML in older patients is still venetoclax with hypomethylation agents, new clinical combinations of glasdegib are being tested in hope of replacing venetoclax due to glasdegib's more favorable side effects profile.A258493

Struktur Molekul 2D

Berat 374.448
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) The reported half-life of glasdegib is of 17.4 hours.[T367]
Volume Distribusi Glasdegib reported volume of distribution in a dose of 50 mg is 225 L.[A173857] The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies.[L45728]
Klirens (Clearance) The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h.[A173857] The geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies.[L45728]

Absorpsi

Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml.A173857 The oral bioavailability of glasdegib is reported to be of 55%.A40310 In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml.A173857 The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal.FDA label

Metabolisme

After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose.A173872

Rute Eliminasi

From a single oral dose of 100 mg radiolabeled glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form.A173872,L45728

Interaksi Makanan

3 Data
  • 1. Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of glasdegib.
  • 2. Take at the same time every day.
  • 3. Take with or without food.

Interaksi Obat

857 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Glasdegib.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Glasdegib.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be increased when it is combined with Glasdegib.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Glasdegib.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Glasdegib.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Glasdegib.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Glasdegib.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Glasdegib.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Glasdegib.
Ranolazine The serum concentration of Ranolazine can be increased when it is combined with Glasdegib.
Silodosin The excretion of Silodosin can be decreased when combined with Glasdegib.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Glasdegib.
Everolimus The serum concentration of Everolimus can be increased when it is combined with Glasdegib.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Glasdegib.
Mifepristone The serum concentration of Glasdegib can be increased when it is combined with Mifepristone.
Vincristine The excretion of Vincristine can be decreased when combined with Glasdegib.
Doxorubicin The serum concentration of Doxorubicin can be increased when it is combined with Glasdegib.
Lumacaftor The serum concentration of Glasdegib can be decreased when it is combined with Lumacaftor.
Leuprolide The risk or severity of QTc prolongation can be increased when Leuprolide is combined with Glasdegib.
Goserelin The risk or severity of QTc prolongation can be increased when Goserelin is combined with Glasdegib.
Erythromycin The risk or severity of QTc prolongation can be increased when Erythromycin is combined with Glasdegib.
Azithromycin The risk or severity of QTc prolongation can be increased when Azithromycin is combined with Glasdegib.
Moxifloxacin The risk or severity of QTc prolongation can be increased when Moxifloxacin is combined with Glasdegib.
Sulfisoxazole The risk or severity of QTc prolongation can be increased when Sulfisoxazole is combined with Glasdegib.
Methadone The risk or severity of QTc prolongation can be increased when Methadone is combined with Glasdegib.
Diltiazem The risk or severity of QTc prolongation can be increased when Diltiazem is combined with Glasdegib.
Clozapine The risk or severity of QTc prolongation can be increased when Glasdegib is combined with Clozapine.
Sulpiride The risk or severity of QTc prolongation can be increased when Sulpiride is combined with Glasdegib.
Nimodipine The risk or severity of QTc prolongation can be increased when Nimodipine is combined with Glasdegib.
Promazine The risk or severity of QTc prolongation can be increased when Promazine is combined with Glasdegib.
Prochlorperazine The risk or severity of QTc prolongation can be increased when Prochlorperazine is combined with Glasdegib.
Droperidol The risk or severity of QTc prolongation can be increased when Droperidol is combined with Glasdegib.
Chlorpromazine The risk or severity of QTc prolongation can be increased when Chlorpromazine is combined with Glasdegib.
Oxaliplatin The risk or severity of QTc prolongation can be increased when Oxaliplatin is combined with Glasdegib.
Ciprofloxacin The risk or severity of QTc prolongation can be increased when Ciprofloxacin is combined with Glasdegib.
Perflutren The risk or severity of QTc prolongation can be increased when Perflutren is combined with Glasdegib.
Cinnarizine The risk or severity of QTc prolongation can be increased when Cinnarizine is combined with Glasdegib.
Atropine The risk or severity of QTc prolongation can be increased when Atropine is combined with Glasdegib.
Chloroquine The risk or severity of QTc prolongation can be increased when Chloroquine is combined with Glasdegib.
Adenosine The risk or severity of QTc prolongation can be increased when Adenosine is combined with Glasdegib.
Pentamidine The risk or severity of QTc prolongation can be increased when Pentamidine is combined with Glasdegib.
Gadobenic acid The risk or severity of QTc prolongation can be increased when Gadobenic acid is combined with Glasdegib.
Carbinoxamine The risk or severity of QTc prolongation can be increased when Carbinoxamine is combined with Glasdegib.
Dolasetron The risk or severity of QTc prolongation can be increased when Dolasetron is combined with Glasdegib.
Roxithromycin The risk or severity of QTc prolongation can be increased when Roxithromycin is combined with Glasdegib.
Nalidixic acid The risk or severity of QTc prolongation can be increased when Nalidixic acid is combined with Glasdegib.
Cinoxacin The risk or severity of QTc prolongation can be increased when Cinoxacin is combined with Glasdegib.
Granisetron The risk or severity of QTc prolongation can be increased when Granisetron is combined with Glasdegib.
Ondansetron The risk or severity of QTc prolongation can be increased when Ondansetron is combined with Glasdegib.
Levosimendan The risk or severity of QTc prolongation can be increased when Levosimendan is combined with Glasdegib.
Mesoridazine The risk or severity of QTc prolongation can be increased when Mesoridazine is combined with Glasdegib.
Desloratadine The risk or severity of QTc prolongation can be increased when Desloratadine is combined with Glasdegib.
Lomefloxacin The risk or severity of QTc prolongation can be increased when Lomefloxacin is combined with Glasdegib.
Dimenhydrinate The risk or severity of QTc prolongation can be increased when Dimenhydrinate is combined with Glasdegib.
Primaquine The risk or severity of QTc prolongation can be increased when Primaquine is combined with Glasdegib.
Papaverine The risk or severity of QTc prolongation can be increased when Papaverine is combined with Glasdegib.
Chlorpheniramine The risk or severity of QTc prolongation can be increased when Chlorpheniramine is combined with Glasdegib.
Nifedipine The risk or severity of QTc prolongation can be increased when Nifedipine is combined with Glasdegib.
Levofloxacin The risk or severity of QTc prolongation can be increased when Levofloxacin is combined with Glasdegib.
Gemifloxacin The risk or severity of QTc prolongation can be increased when Gemifloxacin is combined with Glasdegib.
Ofloxacin The risk or severity of QTc prolongation can be increased when Ofloxacin is combined with Glasdegib.
Propafenone The risk or severity of QTc prolongation can be increased when Propafenone is combined with Glasdegib.
Flecainide The risk or severity of QTc prolongation can be increased when Flecainide is combined with Glasdegib.
Mibefradil The risk or severity of QTc prolongation can be increased when Mibefradil is combined with Glasdegib.
Probucol The risk or severity of QTc prolongation can be increased when Probucol is combined with Glasdegib.
Aceprometazine The risk or severity of QTc prolongation can be increased when Aceprometazine is combined with Glasdegib.
Terlipressin The risk or severity of QTc prolongation can be increased when Terlipressin is combined with Glasdegib.
Prenylamine The risk or severity of QTc prolongation can be increased when Prenylamine is combined with Glasdegib.
Fluspirilene The risk or severity of QTc prolongation can be increased when Fluspirilene is combined with Glasdegib.
Lofexidine The risk or severity of QTc prolongation can be increased when Lofexidine is combined with Glasdegib.
Azimilide The risk or severity of QTc prolongation can be increased when Azimilide is combined with Glasdegib.
Pracinostat The risk or severity of QTc prolongation can be increased when Pracinostat is combined with Glasdegib.
Technetium Tc-99m ciprofloxacin The risk or severity of QTc prolongation can be increased when Technetium Tc-99m ciprofloxacin is combined with Glasdegib.
Garenoxacin The risk or severity of QTc prolongation can be increased when Garenoxacin is combined with Glasdegib.
Tedisamil The risk or severity of QTc prolongation can be increased when Tedisamil is combined with Glasdegib.
Tucidinostat The risk or severity of QTc prolongation can be increased when Tucidinostat is combined with Glasdegib.
Telavancin The risk or severity of QTc prolongation can be increased when Telavancin is combined with Glasdegib.
Nemonoxacin The risk or severity of QTc prolongation can be increased when Nemonoxacin is combined with Glasdegib.
Nilvadipine The risk or severity of QTc prolongation can be increased when Nilvadipine is combined with Glasdegib.
Antazoline The risk or severity of QTc prolongation can be increased when Antazoline is combined with Glasdegib.
Bedaquiline The risk or severity of QTc prolongation can be increased when Bedaquiline is combined with Glasdegib.
Fendiline The risk or severity of QTc prolongation can be increased when Fendiline is combined with Glasdegib.
Eperisone The risk or severity of QTc prolongation can be increased when Eperisone is combined with Glasdegib.
Butriptyline The risk or severity of QTc prolongation can be increased when Butriptyline is combined with Glasdegib.
Lenvatinib The risk or severity of QTc prolongation can be increased when Lenvatinib is combined with Glasdegib.
Melperone The risk or severity of QTc prolongation can be increased when Melperone is combined with Glasdegib.
Benidipine The risk or severity of QTc prolongation can be increased when Benidipine is combined with Glasdegib.
Dexchlorpheniramine maleate The risk or severity of QTc prolongation can be increased when Dexchlorpheniramine maleate is combined with Glasdegib.
Amifampridine The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Glasdegib.
Mocetinostat The risk or severity of QTc prolongation can be increased when Mocetinostat is combined with Glasdegib.
Entinostat The risk or severity of QTc prolongation can be increased when Entinostat is combined with Glasdegib.
Gilteritinib The risk or severity of QTc prolongation can be increased when Gilteritinib is combined with Glasdegib.
CUDC-101 The risk or severity of QTc prolongation can be increased when CUDC-101 is combined with Glasdegib.
Simendan The risk or severity of QTc prolongation can be increased when Simendan is combined with Glasdegib.
Ricolinostat The risk or severity of QTc prolongation can be increased when Ricolinostat is combined with Glasdegib.
Mizolastine The risk or severity of QTc prolongation can be increased when Mizolastine is combined with Glasdegib.
Abexinostat The risk or severity of QTc prolongation can be increased when Abexinostat is combined with Glasdegib.
Oxatomide The risk or severity of QTc prolongation can be increased when Oxatomide is combined with Glasdegib.
Sitafloxacin The risk or severity of QTc prolongation can be increased when Sitafloxacin is combined with Glasdegib.
Sultopride The risk or severity of QTc prolongation can be increased when Sultopride is combined with Glasdegib.

Target Protein

Protein smoothened SMO
Serine/threonine-protein kinase mTOR MTOR

Referensi & Sumber

Synthesis reference: Munchhof MJ, Li Q, Shavnya A, et al. Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened. ACS Med Chem Lett. 2012;3(2):106-11.
Artikel (PubMed)
  • PMID: 24900436
    Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina L, Patel N, Pelletier K, Reiter LA, Robbins MD, Tkalcevic GT: Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened. ACS Med Chem Lett. 2011 Dec 21;3(2):106-11. doi: 10.1021/ml2002423. eCollection 2012 Feb 9.
  • PMID: 28556364
    Minami Y, Minami H, Miyamoto T, Yoshimoto G, Kobayashi Y, Munakata W, Onishi Y, Kobayashi M, Ikuta M, Chan G, Woolfson A, Ono C, Shaik MN, Fujii Y, Zheng X, Naoe T: Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci. 2017 Aug;108(8):1628-1633. doi: 10.1111/cas.13285. Epub 2017 Jun 19.
  • PMID: 22223823
    Irvine DA, Copland M: Targeting hedgehog in hematologic malignancy. Blood. 2012 Mar 8;119(10):2196-204. doi: 10.1182/blood-2011-10-383752. Epub 2012 Jan 5.
  • PMID: 27866461
    Lam JL, Vaz A, Hee B, Liang Y, Yang X, Shaik MN: Metabolism, excretion and pharmacokinetics of (14)Cglasdegib (PF-04449913) in healthy volunteers following oral administration. Xenobiotica. 2017 Dec;47(12):1064-1076. doi: 10.1080/00498254.2016.1261307. Epub 2017 Jan 3.
  • PMID: 35937938
    Iyer SG, Stanchina M, Bradley TJ, Watts J: Profile of Glasdegib for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML): Evidence to Date. Cancer Manag Res. 2022 Aug 1;14:2267-2272. doi: 10.2147/CMAR.S195723. eCollection 2022.
  • PMID: 34661144
    Jamieson C, Martinelli G, Papayannidis C, Cortes JE: Hedgehog Pathway Inhibitors: A New Therapeutic Class for the Treatment of Acute Myeloid Leukemia. Blood Cancer Discov. 2020 Aug 11;1(2):134-145. doi: 10.1158/2643-3230.BCD-20-0007. eCollection 2020 Sep.
  • PMID: 30987263
    Terao T, Minami Y: Targeting Hedgehog (Hh) Pathway for the Acute Myeloid Leukemia Treatment. Cells. 2019 Apr 3;8(4):312. doi: 10.3390/cells8040312.
Textbook
  • Bethesda (2006). Drugs and Lactation Database. National Library of Medicine.

Contoh Produk & Brand

Produk: 8 • International brands: 0
Produk
  • Daurismo
    Tablet • 25 mg • Oral • Canada • Approved
  • Daurismo
    Tablet • 100 mg • Oral • Canada • Approved
  • Daurismo
    Tablet, film coated • 25 mg • Oral • EU • Approved
  • Daurismo
    Tablet, film coated • 25 mg • Oral • EU • Approved
  • Daurismo
    Tablet, film coated • 100 mg • Oral • EU • Approved
  • Daurismo
    Tablet, film coated • 100 mg • Oral • EU • Approved
  • Daurismo
    Tablet, film coated • 25 mg/1 • Oral • US • Approved
  • Daurismo
    Tablet, film coated • 100 mg/1 • Oral • US • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
© 2025 Digital Pharmacy Research - Universitas Esa Unggul