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 cat.
Legal status
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) N
ATC code L01XE08
PubChem CID 644241
DrugBank DB04868
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 
Mol. mass 529.5245 g/mol
 N (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]

Medical uses[edit]

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

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] 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.[13]

Contraindications[edit]

Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance.[1][7]

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

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.[14]

Adverse effects[edit]

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] Though pulmonary-related adverse effects are rare when compare with imatinib and dasatinib. There is a case report of acute respiratory failure from diffuse alveolar hemorrhage in patient taking nilotinib.[15]

Interactions[edit]

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.[14] Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3.[16]

It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors and inducers may interact with nilotinib.[1] Patients report that pomegranates and starfruit may also interfere.

Pharmacology[edit]

Nilotinib inhibits the kinases BCR-ABL,[17] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK.[18]

References[edit]

  1. ^ a b c d e f g h i "Tasigna (nilotinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 25 January 2014. 
  2. ^ Official Manufacturer Website http://www.tasigna.com
  3. ^ "Cancer Drug Information: Nilotinib". 
  4. ^ a b "Complete Nilotinib information from Drugs.com". Drugs.com. Retrieved 25 January 2014. 
  5. ^ "Tasigna : EPAR - Product Information" (PDF). European Medicines Agency. Novartis Europharm Ltd. 18 October 2013. Retrieved 25 January 2014. 
  6. ^ "Tasigna 150mg Hard Capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Novartis Pharmaceuticals UK Ltd. 9 September 2013. Retrieved 25 January 2014. 
  7. ^ a b "TASIGNA® nilotinib" (PDF). TGA eBusiness Services. 21 October 2013. Retrieved 25 January 2014. 
  8. ^ Kantarjian H et al.; Giles, Francis; Wunderle, Lydia; Bhalla, Kapil; O'Brien, Susan; Wassmann, Barbara; Tanaka, Chiaki; Manley, Paul; Rae, Patricia; Mietlowski, William; Bochinski, Kathy; Hochhaus, Andreas; Griffin, James D.; Hoelzer, Dieter; Albitar, Maher; Dugan, Margaret; Cortes, Jorge; Alland, Leila; Ottmann, Oliver G. (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. 
  9. ^ "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. 
  10. ^ "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. 
  11. ^ "Prescribing information for Tasigna (nilotinib) Capsules" (PDF). NDA 022068. U.S. FDA. 2007-10-29. Retrieved 2009-08-04. 
  12. ^ http://medicalxpress.com/news/2013-05-cancer-drug-build-up-toxic-brain.html
  13. ^ http://www.novartis.com/newsroom/media-releases/en/2011/1504991.shtml
  14. ^ a b Khurana V, Minocha M, Pal D, Mitra AK (March 2014). "Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.". Drug Metabol Drug Interact. 0 (0): 1–11. doi:10.1515/dmdi-2013-0062. PMID 24643910. 
  15. ^ Donatelli, Christopher, Daych Chongnarungsin, and Rendell Ashton. "Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage." Leukemia & Lymphoma 0 (2014): 1-6.
  16. ^ Khurana V, Minocha M, Pal D, Mitra AK (May 2014). "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors.". Drug Metabol Drug Interact. 0 (0): 1–11. doi:10.1515/dmdi-2014-0014. PMID 24807167. 
  17. ^ 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. 
  18. ^ 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[edit]