Nilotinib
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|---|---|
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| 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 cat. | D (AU) D (US) |
| Legal status | Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | 30%[1] |
| Protein binding | 98%[1] |
| Metabolism | Hepatic (mostly CYP3A4-mediated)[1] |
| Half-life | 15-17 hours[1] |
| Excretion | Faeces (93%)[1] |
| Identifiers | |
| CAS number | 641571-10-0(base)  |
| ATC code | L01XE08 |
| PubChem | CID 644241 |
| DrugBank | DB04868 |
| ChemSpider | 559260  |
| UNII | F41401512X |
| KEGG | D08953 |
| ChEBI | CHEBI:52172 |
| ChEMBL | CHEMBL255863 |
| Chemical data | |
| Formula | C28H22F3N7O |
| Mol. mass | 529.5245 g/mol |
| SMILES
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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]
Medical uses
It is FDA- (29 October 2007),[4] EMA- (29 September 2009),[5] MHRA- (19 November 2007)[6] and TGA- (17 January 2008)[7] 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.[8] In that study 92% of patients (already resistant or unresponsive to imatinib) achieved a normal white blood cell counts after five months of treatment.[9] The drug carries a black box warning for possible heart complications.[10][11] 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.[12]
Contraindications
Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance.[7][1]
Cautions include:[1]
- 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
Adverse effects
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 effect the body's electrolyte and glucose balance.[4]
Interactions
It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors and inducers may interact with nilotinib.[1]
Pharmacology
Nilotinib inhibits the kinases BCR-ABL,[13] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK.[14]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Tasigna (nilotinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 25 January 2014.
- ↑ Official Manufacturer Website http://www.tasigna.com
- ↑ "Cancer Drug Information: Nilotinib".
- ↑ 4.0 4.1 "Complete Nilotinib information from Drugs.com". Drugs.com. Retrieved 25 January 2014.
- ↑ "Tasigna : EPAR - Product Information" (PDF). European Medicines Agency. Novartis Europharm Ltd. 18 October 2013. Retrieved 25 January 2014.
- ↑ "Tasigna 150mg Hard Capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Novartis Pharmaceuticals UK Ltd. 9 September 2013. Retrieved 25 January 2014.
- ↑ 7.0 7.1 "TASIGNA® nilotinib" (PDF). TGA eBusiness Services. 21 October 2013. Retrieved 25 January 2014.
- ↑ Kantarjian H et al. (2006). "Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL". N Engl J Med 354 (24): 2542–51. doi:10.1056/NEJMoa055104. PMID 16775235.
- ↑ "Patients with treatment-resistant leukemia achieve high responses to Tasigna (nilotinib) in first published clinical trial results". MediaReleases (Novartis). 2006-06-14. Retrieved 2009-08-04.
- ↑ "FDA Approves Tasigna for Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia". U.S. Food and Drug Administration. 2007-10-30. Retrieved 2009-08-04.
- ↑ "Prescribing information for Tasigna (nilotinib) Capsules" (PDF). NDA 022068. U.S. FDA. 2007-10-29. Retrieved 2009-08-04.
- ↑ http://medicalxpress.com/news/2013-05-cancer-drug-build-up-toxic-brain.html
- ↑ Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD (June 2006). "AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL". Br. J. Cancer 94 (12): 1765–9. doi:10.1038/sj.bjc.6603170. PMC 2361347. PMID 16721371.
- ↑ Manley, PW; Drueckes, P; Fendrich, G; Furet, P; Liebetanz, J; Martiny-Baron, G; Mestan, J; Trappe, J et al. (2010). "Extended kinase profile and properties of the protein kinase inhibitor nilotinib". Biochimica et Biophysica Acta 1804 (3): 445–53. doi:10.1016/j.bbapap.2009.11.008. PMID 19922818.
External links
- 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)
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