![]() | |
![]() | |
Clinical data | |
---|---|
Trade names | Tasigna, others |
Other names | AMN107 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a608002 |
License data | |
Pregnancy category |
|
Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 30% [4] |
Protein binding | 98% [4] |
Metabolism | Liver (mostly CYP3A4-mediated) [4] |
Elimination half-life | 15-17 hours [4] |
Excretion | Faeces (93%) [4] |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
PDB ligand | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.166.395 |
Chemical and physical data | |
Formula | C28H22F3N7O |
Molar mass | 529.527 g·mol−1 |
3D model (JSmol) | |
| |
| |
![]() ![]() |
Nilotinib, sold under the brand name Tasigna marketed worldwide by Novartis, is a medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome. [5] It may be used both in initial cases of chronic phase CML as well as in accelerated and chronic phase CML that has not responded to imatinib. [5] [6] It is taken by mouth. [6]
Common side effects may include low platelets, low white blood cells, anemia, rashes, vomiting, diarrhea, and joint pains. [6] Other serious side effects may include QT prolongation, sudden death, pancreatitis, and liver problems. [6] It is not safe for use during pregnancy. [6] Nilotinib is a Bcr-Abl tyrosine kinase inhibitor and works by interfering with signalling within the cancer cell. [6]
Nilotinib was approved for medical use in the United States in 2007. [6] It is on the World Health Organization's List of Essential Medicines. [7] It is approved as a generic medication. [8]
Nilotinib is used to treat Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia. [4]
Nilotinib has a number of adverse effects including headache, fatigue, gastrointestinal problems such as nausea, vomiting, diarrhea and constipation, muscle and joint pain, rash and other skin conditions, flu-like symptoms, and reduced blood cell count. Less typical side effects are those of the cardiovascular system, such as high blood pressure, various types of arrhythmia, and prolonged QT interval. Nilotinib can also affect the body's electrolyte and glucose balance. [9] Though lung-related adverse effects are rare when compared with imatinib and dasatinib, there is a case report of acute respiratory failure from diffuse alveolar hemorrhage in a people taking nilotinib. [10]
Nilotinib carries a black box warning in the United States for possible heart complications. [11] [2] Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance. [4] [12]
Cautions include: [4]
Dose reduction has been recommended in people with liver problems which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities. [13]
Hepatitis B virus reactivation may also occur. [14]
Nilotinib has been reported as a substrate for OATP1B1 and OATP1B3. Interaction of nilotinib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions. [13] Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3. [15]
It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors [16] will increase its action and inducers like St. John's wort [17] will decrease it. Patients report that pomegranates and starfruit may also interfere.
Nilotinib inhibits the kinases BCR-ABL, [18] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK. [19]
Structurally related to imatinib, [20] It is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells. [20] [21] [22] [23]
Nilotinib was developed by Novartis. [6] It was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance. [24] [21] [22]
It was approved for medical use by the FDA in October 2007, [9] EMA in September 2009, [25] MHRA in November 2007, [26] and TGA in January 2008. [12]
There is weak evidence that nilotinib may be beneficial with Parkinson's disease (PD), with a small clinical trial suggesting it might halt progression and improve symptoms. [27] However, there were significant side effects including infection, liver function tests abnormalities, hallucinations and heart attack, and the benefit in PD disappeared at follow up after drug discontinuation, raising question as to whether it was truly a disease modifying therapy. Nilotinib is currently undergoing phase II studies for treatment of Parkinson's. [28] Scientists and medical professionals have advised caution with over-optimistic interpretation of its effects in Parkinson's due to the significant media hype surrounding the small and early clinical trial. [29] [30] Dystonia and cognitive impairment have also been reported as side effects. [31]
Novartis announced in April 2011, that it was discontinuing a phase III trial of nilotinib as the first-line treatment of gastrointestinal stromal tumor (GIST) based on the recommendation of an independent data monitoring committee. Interim results showed Tasigna is unlikely to demonstrate superiority compared to Novartis's Gleevec (imatinib)*, the current standard of care in this setting. [32]
Low dose nilotinib is also being investigated for use in Alzheimer's disease, as well as for ALS, dementia and Huntington's disease. [33]
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signaling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.
Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.
Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome–positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.
Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene, which was initially isolated from the Abelson murine leukemia virus.
Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+). It is taken by mouth.
Vandetanib, sold under the brand name Caprelsa, is an anti-cancer medication that is used for the treatment of certain tumours of the thyroid gland. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor, the epidermal growth factor receptor, and the RET-tyrosine kinase. The drug was developed by AstraZeneca who later sold the rights to Sanofi in 2015.
Pazopanib, sold under the brand name Votrient, is an anti-cancer medication marketed worldwide by Novartis. It is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.
Bosutinib, sold under the brand name Bosulif, is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.
Nicholas B. Lydon FRS is a British scientist and entrepreneur. In 2009, he was awarded the Lasker Clinical Award and in 2012 the Japan Prize for the development of Gleevec, also known as Imatinib, a selective BCR-ABL inhibitor for the treatment of chronic myeloid leukaemia (CML), which converted a fatal cancer into a manageable chronic condition.
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 phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.
Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.
Ponatinib, sold under the brand name Iclusig, is a medication used for the treatment of chronic myeloid leukemia and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia. It was developed by Ariad Pharmaceuticals. It is a multi-targeted tyrosine-kinase inhibitor. Some forms of chronic myeloid leukemia, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.
Canertinib (CI-1033) is an experimental drug candidate for the treatment of cancer. It is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC50 0.8 nM), HER-2 (IC50 19 nM) and ErbB-4 (IC50 7 nM). By 2015, Pfizer had discontinued development of the drug.
Radotinib (INN; trade name Supect), and sometimes referred to by its investigational name IY5511, is a drug for the treatment of different types of cancer, most notably Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) with resistance or intolerance of other Bcr-Abl tyrosine-kinase inhibitors, such as patients resistant or intolerant to imatinib.
Bafetinib (NS-187) is an experimental cancer drug developed by Nippon Shinyaku and licensed to CytRx. It is an inhibitor of Lyn and Bcr-Abl. It reached phase II clinical trials in 2010.
Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.
Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukemia. Asciminib is a protein kinase inhibitor.