|Systematic (IUPAC) name|
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
|Metabolism||Hepatic (mostly CYP3A4-mediated)|
|Biological half-life||15-17 hours|
|ATC code||L01XE08 (WHO)|
|PDB ligand ID||NIL (PDBe, RCSB PDB)|
|Molar mass||529.5245 g/mol|
|(what is this?)|
Nilotinib (AMN107, trade name Tasigna), in the form of the hydrochloride monohydrate salt, is a small-molecule tyrosine kinase inhibitor approved for the treatment of imatinib-resistant chronic myelogenous leukemia. Structurally related to imatinib, it was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance. Nilotinib is a selective Bcr-Abl kinase inhibitor that is 10-30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells.
It is FDA- (29 October 2007), EMA- (29 September 2009), MHRA- (19 November 2007) and TGA- (17 January 2008) approved for use as a treatment for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia.
In June 2006, a phase I clinical trial found nilotinib has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib, another tyrosine kinase inhibitor currently used as a first-line treatment. In that study 92% of patients (already resistant or unresponsive to imatinib) achieved normal white blood cell counts after five months of treatment.
Novartis announced on April 11, 2011 that it is discontinuing a phase III trial of Tasigna® (nilotinib) for investigational use in 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 Glivec® (imatinib)*, the current standard of care in this setting.
Nilotinib is currently being trialed in people with Parkinson's disease as it appears to be able to halt progression of the disease and even improve their symptoms . The researchers behind the trial think that the drug blocks a protein that interferes with the action of lysosomes which normally destroy harmful proteins in the brain.
- Tumour lysis syndrome
- Liver impairment
- History of pancreatitis
- Check serum lipase periodically in order to detect pancreatitis
- Total gastrectomy
- Avoid pregnancy or impregnating women
Dose reduction of nilotinib has been recommended in hepatically impaired population which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities.
Nilotinib has a number of adverse effects typical of anti-cancer drugs. These include 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 hypertension (high blood pressure), various types of arrhythmia, and prolonged QT interval. Nilotinib can also affect the body's electrolyte and glucose balance. Though pulmonary-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 patient taking nilotinib.
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. Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3.
It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inducers will increase its action and inhibitors like St. John's wort will decrease it. Strong pharmaceutical CYP3A4 inducers can triple its action. Patients report that pomegranates and starfruit may also interfere.
Food should not be eaten two hours before or one hour afterwards because it unpredictably increases its bioavailability, approximately doubling it.
- Bcr-Abl tyrosine-kinase inhibitor#Nilotinib (AMN107) re development and resistance
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- Discovery and development of Bcr-Abl tyrosine kinase inhibitors
- New drug information/Abbreviated Scientific Narrative
- Highlights of Prescription information Nilotinib (August 2007) Novartis Pharmaceuticals Corporation (USA)
- Summary of Product Characteristics Nilotinib (November 2007) Novartis AG (Europe)