Nilotinib

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Nilotinib
Nilotinib2DACS.svg
Nilotinib3Dan.gif
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
Clinical data
Trade names Tasigna
AHFS/Drugs.com monograph
MedlinePlus a608002
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 30%[1]
Protein binding 98%[1]
Metabolism Hepatic (mostly CYP3A4-mediated)[1]
Biological half-life 15-17 hours[1]
Excretion Faeces (93%)[1]
Identifiers
CAS Number 641571-10-0(base) N
ATC code L01XE08 (WHO)
PubChem CID: 644241
IUPHAR/BPS 5697
DrugBank DB04868 YesY
ChemSpider 559260 YesY
UNII F41401512X YesY
KEGG D08953 YesY
ChEBI CHEBI:52172 YesY
ChEMBL CHEMBL255863 YesY
PDB ligand ID NIL (PDBe, RCSB PDB)
Chemical data
Formula C28H22F3N7O
Molecular mass 529.5245 g/mol
  • Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)C(=O)Nc4cc(cc(c4)n5cc(nc5)C)C(F)(F)F
  • InChI=1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37) YesY
  • Key:HHZIURLSWUIHRB-UHFFFAOYSA-N YesY
 NYesY (what is this?)  (verify)

Nilotinib (AMN107, trade name Tasigna[2]), 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.[3] Structurally related to imatinib,[4] it was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance.[5][6][7] Nilotinib is a selective Bcr-Abl kinase inhibitor[5][6] that is 10-30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells.[4][6][7][8]

Crystal structure of Abl kinase domain (blue) in complex with nilotinib (red)

Medical uses

Crystal structure of Abl kinase domain (blue) in complex with nilotinib (red)

It is FDA- (29 October 2007),[9] EMA- (29 September 2009),[10] MHRA- (19 November 2007)[11] and TGA- (17 January 2008)[12] approved for use as a treatment for Philadelphia Chromosome (Ph+)-positive Chronic myelogenous leukaemia.[1] 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.[13] In that study 92% of patients (already resistant or unresponsive to imatinib) achieved normal white blood cell counts after five months of treatment.[14] The drug carries a black box warning for possible heart complications.[15][16] The use of low doses of nilotinib is being investigated for use for Parkinson's, and Alzheimer's disease, as well as for ALS, dementia and Huntington's disease.[17] 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.[18]

Contraindications

Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance.[1][12]

Cautions include:[1]

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  • Myelosuppression
  • 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.[19]

Adverse effects

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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.[9] 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.[20]

Interactions

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.[19] Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3.[21]

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.[1] 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.

Pharmacology

Nilotinib inhibits the kinases BCR-ABL,[22] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK.[23]

Other uses

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. [1]

References

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External links

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Lua error in package.lua at line 80: module 'strict' not found.
  2. Official Manufacturer Website http://www.tasigna.com
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  6. 6.0 6.1 6.2 Jabbour, E., Cortes, J., Kantarjian, H. (2009). "Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review". Core evidence 4: 207-213.
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  17. http://medicalxpress.com/news/2013-05-cancer-drug-build-up-toxic-brain.html
  18. http://www.novartis.com/newsroom/media-releases/en/2011/1504991.shtml
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  20. Donatelli, Christopher, Daych Chongnarungsin, and Rendell Ashton. "Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage." Leukemia & Lymphoma 0 (2014): 1-6.
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