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Dacomitinib

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Dacomitinib is a tyrosine kinase inhibitor. A kinase is an enzyme that promotes cell growth. There are many types of kinases, which control different phases of cell growth…

Product Description

Basic Characteristics

Product Name Dacomitinib
CAS Number 1110813-31-4
Molecular Formula C24H25ClFN5O2
Formula Weight 469.9
Synonyms Dacomitinib;

1110813-31-4;

PF299804;

Dacomitinib (PF299804, PF299);

PF-00299804;

(2E)-N-(4-((3-chloro-4-fluorophenyl)Amino)-7-methoxyquinazolin-6-yl)-4-piperidin-1-ylbut-2-enamide.

Appearance White or kind of white powder
Storage and Handling Store at room temperature in a dry place.

 

Dacomitinib Description

Dacomitinib is a tyrosine kinase inhibitor. A kinase is an enzyme that promotes cell growth. There are many types of kinases, which control different phases of cell growth. This medication targets epidermal growth factor receptor (EGFR) tyrosine kinase with exon 19 deletion or exon 21 L858R substitution mutations. By blocking EGFR, this medication can slow the growth of cancer cells. Your oncology team will test your tumor for this abnormality, which must be present in order to receive the medication.

 

Dacomitinib Mechanism of Action

Dacomitinib is an irreversible small molecule inhibitor of the activity of the human epidermal growth factor receptor (EGFR) family (EGFR/HER1, HER2, and HER4) tyrosine kinases. It achieves irreversible inhibition via covalent bonding to the cysteine residues in the catalytic domains of the HER receptors.The affinity of dacomitinib has been shown to have an IC50 of 6 nmol/L.

The ErbB or epidermal growth factor (EGF) family plays a role in tumor growth, metastasis, and treatment resistance by activating downstream signal transduction pathways such as such as Ras-Raf-MAPK, PLCgamma-PKC-NFkB and PI3K/AKT through the tyrosine kinase-driven phosphorylation at the carboxy-terminus.Around 40% of cases show amplification of EGFR gene and 50% of the cases present the EGFRvIII mutation which represents a deletion that produces a continuous activation of the tyrosine kinase domain of the receptor.

 

Dacomitinib Application

Dacomitinib is used to treat a certain type of lung cancer (non-small cell lung cancer). It works by slowing or stopping the growth of cancer cells.

Dacomitinib was approved for medical use in the United States in September 2018,in Japan in 2019, and in the European Union in 2019,for the treatment of non-small cell lung cancer with epidermal growth factor receptor (EGFR) gene mutation.

 

Dacomitinib Side Effects & Warning

Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

▪ Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

▪ Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.

▪ Signs of electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up.

▪ Any skin reaction.

▪ Redness or irritation of the palms of hands or soles of feet.

▪ Chest pain.

▪ Fever.

▪ Very bad and sometimes deadly lung problems have happened with dacomitinib. Call your doctor right away if you have lung or breathing problems that are new or worse like cough or shortness of breath.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.You may report side effects to the FDA at 1-800-332-1088.

 

Reference

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[2] Janne PA, Boss DS, Camidge DR, Britten CD, Engelman JA, Garon EB, Guo F, Wong S, Liang J, Letrent S, Millham R, Taylor I, Eckhardt SG, Schellens JH: Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res. 2011 Mar 1;17(5):1131-9. doi: 10.1158/1078-0432.CCR-10-1220. Epub 2011 Jan 10.

[3] Smith M (6 June 2017). “Dacomitinib Sets PFS Record in Phase III NSCLC Trial”. MedPage Today.

[4] Taylor P (28 January 2014). “Blow to Pfizer as dacomitinib fails in lung cancer trials”. pmlive.com.

[5] Sepulveda JM, Sanchez-Gomez P, Vaz Salgado MA, Gargini R, Balana C: Dacomitinib: an investigational drug for the treatment of glioblastoma. Expert Opin Investig Drugs. 2018 Oct;27(10):823-829. doi: 10.1080/13543784.2018.1528225. Epub 2018 Oct 5.

[6] Bethune G, Bethune D, Ridgway N, Xu Z: Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010 Mar;2(1):48-51.

[7] Bethesda (2006). Drugs and Lactation Database. National Library of Medicine.

[8] Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE, Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood V, Smaill JB, Trumpp-Kallmeyer S, Dobrusin EM: Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):12022-7.