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Neratinib (
INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...
), sold under the brand name Nerlynx, is a
tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...
anti-cancer medication Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cu ...
used for the treatment of breast cancer. The most common side effect is diarrhea, which affects nearly all patients. Other common side effects include nausea (feeling sick), vomiting, tiredness, belly pain, rash, decreased appetite, stomatitis (sore, inflamed mouth), and muscle spasms.


Medical uses

In the European Union and the United States, neratinib is
indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
for the extended adjuvant treatment of adults with early stage (human epidermal growth factor receptor 2) HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy. In the United States, it is also indicated, in combination with
capecitabine Capecitabine, sold under the brand name Xeloda among others, is a anticancer medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth. ...
, 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.


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.


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 Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function ...
. Similarly, there is a risk of severe
liver damage Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground glas ...
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 Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
. 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.


Interactions

People taking neratinib should avoid concurrent use of gastric acid–reducing agents, including
proton pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. The body eventually synthesizes ne ...
s and
H2-receptor antagonist H2 antagonists, sometimes referred to as H2RAs and also called H2 blockers, are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of stomac ...
s.
Antacid An antacid is a substance which neutralization (chemistry), neutralizes gastric acid, stomach acidity and is used to relieve heartburn, indigestion, or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhe ...
s may be taken at least three hours before or after administration of neratinib. Drugs that inhibit
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
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 P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
and effectively raises the dose of drugs like
digoxin Digoxin (better known as digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...
that depend on it for elimination.


Pharmacology

Like
lapatinib Lapatinib (INN), used in the form of lapatinib ditosylate ( USAN) (trade names Tykerb and Tyverb marketed by Novartis) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts ...
and
afatinib Afatinib, sold under the brand name Gilotrif among others, is a medication which is used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth. It is mainly us ...
, it is a dual inhibitor of the human epidermal growth factor receptor 2 (Her2) and
epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor (biochemistry), receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligand (biochemistry ...
(EGFR) kinases. It inhibits them by covalently binding with a cysteine side chain in those proteins. Unlike related noncovalent inhibitors, neratinib is effective against the
T790M T790M, also known as Thr790Met, is a gatekeeper mutation of the epidermal growth factor receptor (EGFR). The mutation substitutes a threonine (T) with a methionine (M) at position 790 of exon 20, affecting the ATP binding pocket of the EGFR kinas ...
resistant variant of EGFR. 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. 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 SK-OV-3 (also known as SKOV-3; SK.OV.3; SKOV3; Skov3 and SKO3) is an ovarian cancer cell line derived from the ascites of a 64-year-old Caucasian female with an ovarian serous cystadenocarcinoma Cystadenocarcinoma is a malignant tumor that arises fr ...
models doses of 5 and 60 mg/kg significantly inhibited tumor growth.


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.


Chemistry

Neratinib is a 4-anilino-3-cyano quinoline derivative.


History

Neratinib was discovered and initially developed by
Wyeth Wyeth Pharmaceuticals Inc. was a pharmaceutical company until it was purchased by Pfizer in 2009. The company was founded in Philadelphia, Pennsylvania, in 1860 as John Wyeth and Brother. Its headquarters moved to Collegeville, Pennsylvania, a ...
;
Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...
continued development up to Phase III in breast cancer, and licensed it to Puma Biotechnology in 2011. It was approved for medical use in the United States in July 2017, for the extended
adjuvant treatment In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analges ...
of adults with early stage
HER2 Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The ...
-overexpressed/amplified breast cancer, (after adjuvant trastuzumab-based therapy). Approval was based on the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment. Neratinib was approved for medical use in the European Union in August 2018. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.


Brand names

In Bangladesh it is sold under the trade name Hernix.


References


External links

* * * * * {{Portal bar , Medicine Alkene derivatives Aromatic amines Carboxamides Chloroarenes Nitriles Phenol ethers 2-Pyridyl compounds Quinolines Receptor tyrosine kinase inhibitors Dimethylamino compounds