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Neratinib
Clinical data
Trade names	Nerlynx, Hernix
Other names	HKI-272
AHFS/Drugs.com	Monograph
MedlinePlus	a617034
License data	EU EMA: by INN; US DailyMed: Neratinib; US FDA: Nerlynx;
Pregnancy; category	AU: D; ;
Routes of; administration	By mouth
Drug class	Antineoplastic agent
ATC code	L01EH02 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only; EU: Rx-only;
Identifiers
	IUPAC name (2E)-N-[4-[[3-Chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide;
CAS Number	698387-09-6 ;
PubChem CID	9915743;
IUPHAR/BPS	5686;
DrugBank	DB11828 ;
ChemSpider	8091392 ;
UNII	JJH94R3PWB;
KEGG	D08950 ; as salt: D10898 ;
ChEMBL	ChEMBL180022 ;
CompTox Dashboard (EPA)	DTXSID70220132 ;
ECHA InfoCard	100.241.512
Chemical and physical data
Formula	C30H29ClN6O3
Molar mass	557.05 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)C=CCN(C)C;
	InChI InChI=1S/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+ ; Key:JWNPDZNEKVCWMY-VQHVLOKHSA-N ;
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Neratinib (INN), sold under the brand name Nerlynx, is a tyrosine kinase inhibitor anti-cancer medication used for the treatment of breast cancer.^[3]^[4]

The most common side effect is diarrhea, which affects nearly all patients.^[4] Other common side effects include nausea (feeling sick), vomiting, tiredness, belly pain, rash, decreased appetite, stomatitis (sore, inflamed mouth), and muscle spasms.^[4]

Medical uses

In the European Union and the United States, neratinib is indicated for the extended adjuvant treatment of adults with early stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy.^[3]^[4]

In the United States, it is also indicated, in combination with capecitabine, for the treatment of adults with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.^[3]

Contraindications

Women who are pregnant should not take it, and women should not become pregnant while taking it, and women who are breast-feeding should not use it, as it can cause harm to the fetus and to the baby.^[3]

Adverse effects

Neratinib can cause life-threatening diarrhea in some people and mild to moderate diarrhea in almost everyone; people who take it are also at risk for complications of diarrhea like dehydration and electrolyte imbalance.^[3] Similarly, there is a risk of severe liver damage and many patients have some level of it; symptoms of liver damage include fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and high levels of eosinophils.^[3]

In addition to the above, more than 10% of people taking it have nausea, abdominal pain, vomiting, sores on their lips, stomach upset, decreased appetite, rashes, and muscle spasms.^[3]

Interactions

People taking neratinib should not also take gastric acid reducing agents including proton pump inhibitors and H2-receptor antagonists; antacids may be used three hours before of after taking it.^[3]

Drugs that inhibit CYP3A4 increase the activity of neratinib and can make adverse effects worse, and drugs that induce CYP3A4 make neratinib less active and can reduce its efficacy. Neratinib also inhibits p-glycoprotein and effectively raises the dose of drugs like digoxin that depend on it for elimination.^[3]

Pharmacology

Like lapatinib and afatinib, it is a dual inhibitor of the human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases.^[5]^[6] It inhibits them by covalently binding with a cysteine side chain in those proteins.^[7] Unlike related noncovalent inhibitors, neratinib is effective against the T790M resistant variant of EGFR.^[8]

Neratinib has an IC₅₀ of 59 nM against HER2 and shows weak inhibition against KDR and Scr with IC₅₀ values of 0.8 μM and 1.4 μM, respectively. In BT474 cells, neratinib reduces HER2 autophosphorylation, and inhibited cyclin D1 expression while reduced proliferation has been observed A431 cells when treated with neratinib at concentrations of 3 or 5 nM.^[9] In xenograft models with 3T3/neu tumors oral administration of neratinib at 10, 20, 40 or 80 mg/kg was able to inhibit tumor growth while in SK-OV-3 models doses of 5 and 60 mg/kg significantly inhibited tumor growth.^[10]

Cell Biology

Neratinib is found to strongly reduce the amount of HER2 released by extracellular vescicles and to enhance the capacity of clathrin mediated endocytosis. However, despite HER2 mediated signaling downregulation, Neratinib exerts only a modest effect on HER2 trafficking at IC50 of 6nM in SKBR3 cells. ^[11]

Chemistry

Neratinib is a 4-anilino-3-cyano quinoline derivative.^[3]

History

Neratinib was discovered and initially developed by Wyeth; Pfizer continued development up to Phase III in breast cancer, and licensed it to Puma Biotechnology in 2011.^[12]

It was approved for medical use in the United States in July 2017, for the extended adjuvant treatment of adults with early stage HER2-overexpressed/amplified breast cancer, (after adjuvant trastuzumab-based therapy).^[13]^[14]^[15] Approval was based on the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment.^[14]^[15]^[16]

Neratinib was approved for medical use in the European Union in August 2018.^[4]

Brand names

In Bangladesh it is sold under the trade name Hernix.^[17]

References

^ "Summary Basis of Decision (SBD) for Nerlynx". Health Canada. 23 October 2014. Retrieved 29 May 2022.
^ "Nerlynx 40 mg Film-coated Tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 13 November 2020.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k "Nerlynx- neratinib tablet". DailyMed. 6 August 2020. Retrieved 13 November 2020.
^ ^a ^b ^c ^d ^e ^f "Nerlynx EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 13 November 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ Baselga J, Coleman RE, Cortés J, Janni W (November 2017). "Advances in the management of HER2-positive early breast cancer". Critical Reviews in Oncology/Hematology. 119: 113–122. doi:10.1016/j.critrevonc.2017.10.001. PMC 5662944. PMID 29042085.
^ Minami Y, Shimamura T, Shah K, LaFramboise T, Glatt KA, Liniker E, et al. (July 2007). "The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272". Oncogene. 26 (34): 5023–5027. doi:10.1038/sj.onc.1210292. PMID 17311002.
^ Singh J, Petter RC, Baillie TA, Whitty A (April 2011). "The resurgence of covalent drugs". Nature Reviews. Drug Discovery. 10 (4): 307–317. doi:10.1038/nrd3410. PMID 21455239. S2CID 5819338.
^ Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. (February 2008). "The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP". Proceedings of the National Academy of Sciences of the United States of America. 105 (6): 2070–2075. Bibcode:2008PNAS..105.2070Y. doi:10.1073/pnas.0709662105. PMC 2538882. PMID 18227510.
^ Schwab CL, English DP, Black J, Bellone S, Lopez S, Cocco E, et al. (October 2015). "Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo". Gynecologic Oncology. 139 (1): 112–117. doi:10.1016/j.ygyno.2015.08.002. PMC 4587290. PMID 26260909.
^ Ma Y, Lin Z, Fallon JK, Zhao Q, Liu D, Wang Y, Liu F (November 2015). "New mouse xenograft model modulated by tumor-associated fibroblasts for human multi-drug resistance in cancer". Oncology Reports. 34 (5): 2699–2705. doi:10.3892/or.2015.4265. PMC 4583831. PMID 26352907.
^ Santamaria S, Gagliani MC, Bellese G, Marconi S, Lechiara A, Dameri M, et al. (July 2021). "Imaging of Endocytic Trafficking and Extracellular Vesicles Released Under Neratinib Treatment in ERBB2⁺ Breast Cancer Cells". The Journal of Histochemistry and Cytochemistry. 69 (7): 461–473. doi:10.1369/00221554211026297. PMC 8246527. PMID 34126793.
^ "Puma Acquires Global Rights to Pfizer's Phase III Breast Cancer Drug Neratinib". GEN. 6 October 2011.
^ "Nerlynx (neratinib maleate) Tablets". U.S. Food and Drug Administration (FDA). 21 August 2017. Retrieved 13 November 2020.
^ ^a ^b "FDA approves new treatment to reduce the risk of breast cancer returning". U.S. Food and Drug Administration (FDA) (Press release). 17 July 2017. Retrieved 13 November 2020. This article incorporates text from this source, which is in the public domain.
^ ^a ^b "FDA approves neratinib for extended adjuvant treatment of early stage HER2-positive breast cancer". U.S. Food and Drug Administration (FDA). 17 July 2017. Retrieved 13 November 2020. This article incorporates text from this source, which is in the public domain.
^ "Drug Trials Snapshot: Nerlynx". U.S. Food and Drug Administration (FDA). 17 July 2017. Retrieved 13 November 2020. This article incorporates text from this source, which is in the public domain.
^ "Hernix". medex.com.bd. Retrieved 14 July 2021.

External links

"Neratinib". Drug Information Portal. U.S. National Library of Medicine.
"Neratinib maleate". Drug Information Portal. U.S. National Library of Medicine.
"Neratinib maleate". National Cancer Institute. 27 July 2017.
"Neratinib maleate". NCI Drug Dictionary. National Cancer Institute.
Clinical trial number NCT00878709 for "Study Evaluating The Effects Of Neratinib After Adjuvant Trastuzumab In Women With Early Stage Breast Cancer (ExteNET)" at ClinicalTrials.gov