请输入您要查询的百科知识：

　

词条 Nilotinib
释义

  1. Medical uses

  2. Clinical trials

     CML  Other 

  3. Contraindications

  4. Adverse effects

  5. Interactions

  6. Pharmacology

  7. See also

  8. References

  9. External links

{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 458285977
| IUPAC_name = 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
| image = Nilotinib2DACS.svg
| width = 300
| image2 = Nilotinib3Dan.gif
| width2 = 250
| tradename = Tasigna
| Drugs.com = {{drugs.com|monograph|nilotinib}}
| MedlinePlus = a608002
| licence_EU = yes
| licence_US = Nilotinib
| pregnancy_AU = D
| pregnancy_US = D
| pregnancy_category =
| legal_AU = S4
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only
| legal_status =
| routes_of_administration = Oral
| bioavailability = 30%[1]
| protein_bound = 98%[1]
| metabolism = Hepatic (mostly CYP3A4-mediated)[1]
| elimination_half-life = 15-17 hours[1]
| excretion = Faeces (93%)[1]
| IUPHAR_ligand = 5697
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 641571-10-0(base)
| ATC_prefix = L01
| ATC_suffix = XE08
| PubChem = 644241
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB04868
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 559260
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = F41401512X
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08953
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 52172
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 255863
| PDB_ligand = NIL
| C=28 | H=22 | F=3 | N=7 | O=1
| molecular_weight = 529.5245 g/mol
| smiles = Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)C(=O)Nc4cc(cc(c4)n5cc(nc5)C)C(F)(F)F
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = HHZIURLSWUIHRB-UHFFFAOYSA-N
}}Nilotinib (AMN107, trade name Tasigna[1]), 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.[2] Structurally related to imatinib,[3] it was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance.[4][5][6] Nilotinib is a selective Bcr-Abl tyrosine kinase inhibitor[4][5] that is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells.[3][5][6][7] Nilotinib was developed by Novartis and is sold under the trade name Tasigna.[8]

Medical uses

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.[13]

The drug carries a black box warning for possible heart complications.[14][15]

Clinical trials

CML

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.[16] In that study 92% of patients (already resistant or unresponsive to imatinib) achieved normal white blood cell counts after five months of treatment.[17]

Other

Novartis announced on April 11, 2011 that it was 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 Gleevec (imatinib)*, the current standard of care in this setting.[18]

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.[19]

Beginning in 2015, nilotinib was being trialed in people with Parkinson's disease as it appeared to be able to halt progression of the disease and even improve their symptoms. The researchers behind the trial hypothesized that the drug blocks a protein that interferes with the action of lysosomes, which in turn normally destroy harmful protein aggregates in the brain.[20]

Contraindications

Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance.[13][12]

Cautions include:[13]

{{div col|colwidth=18em}}
  • 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
{{div col end}}

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.[21]

Adverse effects

{{See also|List of adverse effects of nilotinib}}

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.[22]

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.[21] Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3.[23]

It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors[24] will increase its action and inducers like St. John's wort[25] will decrease it. 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,[26] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK.[27]

See also

  • Bcr-Abl tyrosine-kinase inhibitor#Nilotinib (AMN107) re development and resistance.

References

1. ^Official Manufacturer Website http://www.tasigna.com
2. ^{{cite web|url=http://www.cancer.gov/cancertopics/druginfo/nilotinib|title=Cancer Drug Information: Nilotinib}}
3. ^1 {{Cite journal| last1 = Manley | first1 = P.| last2 = Cowan-Jacob | first2 = S.| last3 = Mestan | first3 = J.| title = Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia| journal = Biochimica et Biophysica Acta| volume = 1754| issue = 1–2| pages = 3–13| year = 2005| pmid = 16172030| doi = 10.1016/j.bbapap.2005.07.040}}
4. ^1 {{Cite journal| last1 = Manley | first1 = P.| last2 = Stiefl | first2 = N.| last3 = Cowan-Jacob | first3 = S.| last4 = Kaufman | first4 = S.| last5 = Mestan | first5 = J.| last6 = Wartmann | first6 = M.| last7 = Wiesmann | first7 = M.| last8 = Woodman | first8 = R.| last9 = Gallagher | first9 = N.| title = Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib| journal = Bioorganic & Medicinal Chemistry| volume = 18| issue = 19| pages = 6977–6986| year = 2010| pmid = 20817538| doi = 10.1016/j.bmc.2010.08.026}}
5. ^1 2 {{cite journal | last1 = Jabbour | first1 = E. | last2 = Cortes | first2 = J. | last3 = Kantarjian | first3 = H. | year = 2009 | title = Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review | url = | journal = Core Evidence | volume = 4 | issue = | pages = 207–213 }}
6. ^1 {{Cite journal| last1 = Olivieri | first1 = A.| last2 = Manzione | first2 = L.| title = Dasatinib: a new step in molecular target therapy| journal = Annals of Oncology| volume = 18 Suppl 6| pages = vi42–vi46| year = 2007| pmid = 17591830| doi = 10.1093/annonc/mdm223}}
7. ^{{Cite journal| last1 = Breccia | first1 = M.| last2 = Alimena | first2 = G.| title = Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia| journal = Leukemia Research| volume = 34| issue = 2| pages = 129–134| year = 2010| pmid = 19783301| doi = 10.1016/j.leukres.2009.08.031}}
8. ^https://www.cancer.gov/about-cancer/treatment/drugs/fda-nilotinib
9. ^1 {{cite web|title=Complete Nilotinib information from Drugs.com|work=Drugs.com|accessdate=25 January 2014|url=https://www.drugs.com/ppa/nilotinib.html}}
10. ^{{cite web|title=Tasigna : EPAR - Product Information|work=European Medicines Agency|publisher=Novartis Europharm Ltd.|date=18 October 2013|accessdate=25 January 2014|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000798/WC500034394.pdf|format=PDF}}
11. ^{{cite web|publisher=Novartis Pharmaceuticals UK Ltd|work=electronic Medicines Compendium|title=Tasigna 150mg Hard Capsules - Summary of Product Characteristics (SPC)|date=9 September 2013|accessdate=25 January 2014|url=http://www.medicines.org.uk/emc/medicine/24089/SPC/Tasigna+150mg+Hard+Capsules/}}
12. ^1 {{cite web|title=TASIGNA® nilotinib|work=TGA eBusiness Services|publisher=21 October 2013|accessdate=25 January 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00292-3|format=PDF}}
13. ^1 2 3 4 5 6 7 {{cite web|title=Tasigna (nilotinib) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|accessdate=25 January 2014|url=http://reference.medscape.com/drug/tasigna-nilotinib-342198#showall}}
14. ^{{cite news|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109017.htm|title=FDA Approves Tasigna for Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia|date=2007-10-30|publisher=U.S. Food and Drug Administration|accessdate=2009-08-04}}
15. ^{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf|title=Prescribing information for Tasigna (nilotinib) Capsules|date=2007-10-29|work=NDA 022068|publisher=U.S. FDA|accessdate=2009-08-04|format=PDF}}
16. ^{{cite journal | author = Kantarjian H | title = Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL | journal = N Engl J Med | volume = 354 | issue = 24 | pages = 2542–51 | year = 2006 | pmid = 16775235 | doi = 10.1056/NEJMoa055104| last2 = Giles | first2 = Francis | last3 = Wunderle | first3 = Lydia | last4 = Bhalla | first4 = Kapil | last5 = O'Brien | first5 = Susan | last6 = Wassmann | first6 = Barbara | last7 = Tanaka | first7 = Chiaki | last8 = Manley | first8 = Paul | last9 = Rae | first9 = Patricia | last10 = Mietlowski | first10 = William | last11 = Bochinski | first11 = Kathy | last12 = Hochhaus | first12 = Andreas | last13 = Griffin | first13 = James D. | last14 = Hoelzer | first14 = Dieter | last15 = Albitar | first15 = Maher | last16 = Dugan | first16 = Margaret | last17 = Cortes | first17 = Jorge | last18 = Alland | first18 = Leila | last19 = Ottmann | first19 = Oliver G. |display-authors=etal}}
17. ^{{cite news|url=http://cws.huginonline.com/N/134323/PR/200606/1056533_5.html|title=Patients with treatment-resistant leukemia achieve high responses to Tasigna (nilotinib) in first published clinical trial results|date=2006-06-14|work=MediaReleases|publisher=Novartis|accessdate=2009-08-04}}
18. ^http://www.novartis.com/newsroom/media-releases/en/2011/1504991.shtml
19. ^{{cite web|title=Cancer drug prevents build-up of toxic brain protein|url=https://medicalxpress.com/news/2013-05-cancer-drug-build-up-toxic-brain.html|publisher=MedicalXpress.com|accessdate=11 April 2017|date=10 May 2013}}
20. ^{{cite web|last1=Hamzelou|first1=Jessica|title=People with Parkinson’s walk again after promising drug trial|url=https://www.newscientist.com/article/dn28357-people-with-parkinsons-walk-again-after-promising-drug-trial/|publisher=New Scientist|accessdate=11 April 2017|date=17 October 2015}}
21. ^1 {{cite journal | vauthors = Khurana V, Minocha M, Pal D, Mitra AK | title = Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors. | journal = Drug Metabol Drug Interact. | volume = 29| issue = 3 | pages = 1–11 |date=March 2014 | pmid = 24643910 | doi = 10.1515/dmdi-2013-0062 | pmc=4407685}}
22. ^{{cite journal | last1 = Donatelli | first1 = Christopher | last2 = Chongnarungsin | first2 = Daych | last3 = Ashton | first3 = Rendell | year = 2014 | title = Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage | journal = Leukemia & Lymphoma | volume = 55| issue = 10| pages = 1–6 | pmid=24467220 | doi=10.3109/10428194.2014.887714}}
23. ^{{cite journal | vauthors = Khurana V, Minocha M, Pal D, Mitra AK | title = Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors. | journal = Drug Metabol Drug Interact. | volume = 29| issue = 4 | pages = 1–11 |date=May 2014 | pmid = 24807167 | doi = 10.1515/dmdi-2014-0014 | pmc=4407688}}
24. ^{{Cite journal|last=Bailey|first=David G|last2=Malcolm|first2=J|last3=Arnold|first3=O|last4=David Spence|first4=J|date=1998-08-01|title=Grapefruit juice–drug interactions|journal=British Journal of Clinical Pharmacology|volume=46|issue=2|pages=101–110|doi=10.1046/j.1365-2125.1998.00764.x|issn=0306-5251|pmc=1873672|pmid=9723817}}
25. ^{{Cite journal|last=Komoroski|first=Bernard J.|last2=Zhang|first2=Shimin|last3=Cai|first3=Hongbo|last4=Hutzler|first4=J. Matthew|last5=Frye|first5=Reginald|last6=Tracy|first6=Timothy S.|last7=Strom|first7=Stephen C.|last8=Lehmann|first8=Thomas|last9=Ang|first9=Catharina Y. W.|date=2004-05-01|title=Induction and inhibition of cytochromes P450 by the St. John's wort constituent hyperforin in human hepatocyte cultures|journal=Drug Metabolism and Disposition|volume=32|issue=5|pages=512–518|doi=10.1124/dmd.32.5.512|issn=0090-9556|pmid=15100173}}
26. ^{{cite journal |vauthors=Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD |title=AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL |journal=Br. J. Cancer |volume=94 |issue=12 |pages=1765–9 |date=June 2006 |pmid=16721371 |doi=10.1038/sj.bjc.6603170 |pmc=2361347}}
27. ^{{cite journal|pmid=19922818|year=2010|last1=Manley|first1=PW|last2=Drueckes|first2=P|last3=Fendrich|first3=G|last4=Furet|first4=P|last5=Liebetanz|first5=J|last6=Martiny-Baron|first6=G|last7=Mestan|first7=J|last8=Trappe|first8=J|last9=Wartmann|first9=M|last10=Fabbro|first10=Doriano|title=Extended kinase profile and properties of the protein kinase inhibitor nilotinib|volume=1804|issue=3|pages=445–53|doi=10.1016/j.bbapap.2009.11.008|journal=Biochimica et Biophysica Acta|display-authors=8}}

External links

  • Discovery and development of Bcr-Abl tyrosine kinase inhibitors
  • New drug information/Abbreviated [https://web.archive.org/web/20121111182229/http://oncozine.com/page/nilotinib-tasignar-novartis Scientific Narrative]
  • Highlights of Prescription information Nilotinib (August 2007) Novartis Pharmaceuticals Corporation (USA)
  • Summary of Product Characteristics Nilotinib (November 2007) Novartis AG (Europe)
{{Extracellular chemotherapeutic agents}}{{Growth factor receptor modulators}}

7 : Orphan drugs|Non-receptor tyrosine kinase inhibitors|Imidazoles|Trifluoromethyl compounds|Benzanilides|Pyrimidines|Pyridines
随便看

　

开放百科全书收录14589846条英语、德语、日语等多语种百科知识，基本涵盖了大多数领域的百科知识，是一部内容自由、开放的电子版国际百科全书。

　

Copyright © 2023 OENC.NET All Rights Reserved
京ICP备2021023879号 更新时间：2024/9/30 22:32:26