nilotinib

Nilotinib is used to treat Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia.{{cite web|title=Tasigna (nilotinib) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=January 25, 2014|url=http://reference.medscape.com/drug/tasigna-nilotinib-342198#showall|archive-date=July 17, 2021|archive-url=https://web.archive.org/web/20210717095516/https://reference.medscape.com/drug/tasigna-nilotinib-342198#showall|url-status=live}} It is indicated for the treatment of newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase; adults with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia resistant to or intolerant to prior therapy that included imatinib; and children with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia resistant or intolerant to prior tyrosine-kinase inhibitor therapy.

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

Nilotinib has a number of adverse effects including 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 high blood pressure, various types of arrhythmia, and prolonged QT interval. Nilotinib can also affect the body's electrolyte and glucose balance. Though lung-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 people taking nilotinib.{{cite journal | vauthors = Donatelli C, Chongnarungsin D, Ashton R | title = Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage | journal = Leukemia & Lymphoma | volume = 55 | issue = 10 | pages = 2408–2409 | date = October 2014 | pmid = 24467220 | doi = 10.3109/10428194.2014.887714 | s2cid = 43118790 }}

Nilotinib carries a black box warning in the United States for possible heart complications.{{cite news|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109017.htm|title=FDA Approves Tasigna for Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia|date=October 30, 2007|publisher=U.S. Food and Drug Administration|access-date=August 4, 2009|archive-date=August 27, 2009|archive-url=https://web.archive.org/web/20090827015037/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109017.htm|url-status=dead}} Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance.

Cautions include:

{{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 has been recommended in people with liver problems which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities.{{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 Metabolism and Drug Interactions | volume = 29 | issue = 3 | pages = 179–190 | date = March 2014 | pmid = 24643910 | pmc = 4407685 | doi = 10.1515/dmdi-2013-0062 }}

Hepatitis B virus reactivation may also occur.{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=978-0-85711-338-2|pages=960|edition=76}}

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.{{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 Metabolism and Drug Interactions | volume = 29 | issue = 4 | pages = 249–259 | date = May 2014 | pmid = 24807167 | pmc = 4407688 | doi = 10.1515/dmdi-2014-0014 }}

It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors{{cite journal | vauthors = Bailey DG, Malcolm J, Arnold O, Spence JD | title = Grapefruit juice-drug interactions | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 2 | pages = 101–110 | date = August 1998 | pmid = 9723817 | pmc = 1873672 | doi = 10.1046/j.1365-2125.1998.00764.x }} will increase its action and inducers like St. John's wort{{cite journal | vauthors = Komoroski BJ, Zhang S, Cai H, Hutzler JM, Frye R, Tracy TS, Strom SC, Lehmann T, Ang CY, Cui YY, Venkataramanan R | 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 | date = May 2004 | pmid = 15100173 | doi = 10.1124/dmd.32.5.512 }} will decrease it. Patients report that pomegranates and starfruit may also interfere.

File:3CS9 Abl1 Nilotinib.png (blue) in complex with nilotinib (red)]]

Nilotinib inhibits the kinases BCR-ABL,{{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 = British Journal of Cancer | volume = 94 | issue = 12 | pages = 1765–1769 | date = June 2006 | pmid = 16721371 | pmc = 2361347 | doi = 10.1038/sj.bjc.6603170 }} KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK.{{cite journal | vauthors = Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, Mestan J, Trappe J, Wartmann M, Fabbro D | title = Extended kinase profile and properties of the protein kinase inhibitor nilotinib | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1804 | issue = 3 | pages = 445–453 | date = March 2010 | pmid = 19922818 | doi = 10.1016/j.bbapap.2009.11.008 }}

Structurally related to imatinib,{{cite journal | vauthors = Manley PW, Cowan-Jacob SW, Mestan 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 (BBA) - Proteins and Proteomics | volume = 1754 | issue = 1–2 | pages = 3–13 | date = December 2005 | pmid = 16172030 | doi = 10.1016/j.bbapap.2005.07.040 }} it is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells.{{cite journal | vauthors = Breccia M, Alimena G | title = Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia | journal = Leukemia Research | volume = 34 | issue = 2 | pages = 129–134 | date = February 2010 | pmid = 19783301 | doi = 10.1016/j.leukres.2009.08.031 }}

{{see also|Discovery and development of Bcr-Abl tyrosine kinase inhibitors}}

Nilotinib was developed by Novartis. It was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance.{{cite journal | vauthors = Manley PW, Stiefl N, Cowan-Jacob SW, Kaufman S, Mestan J, Wartmann M, Wiesmann M, Woodman R, Gallagher 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 | date = October 2010 | pmid = 20817538 | doi = 10.1016/j.bmc.2010.08.026 }}{{cite journal | vauthors = Jabbour E, Cortes J, Kantarjian H | title = Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review | journal = Core Evidence | volume = 4 | pages = 207–213 | date = June 2010 | pmid = 20694077 | pmc = 2899790 | doi = 10.2147/CE.S6003 | doi-access = free }}{{cite journal | vauthors = Olivieri A, Manzione L | title = Dasatinib: a new step in molecular target therapy | journal = Annals of Oncology | volume = 18 | issue = Suppl 6 | pages = vi42–vi46 | date = June 2007 | pmid = 17591830 | doi = 10.1093/annonc/mdm223 | doi-access = free }}

It was approved for medical use by the US Food and Drug Administration (FDA) in October 2007,{{cite web | title=Drug Approval Package: Tasigna (Nilotinib) NDA #022068 | website=U.S. Food and Drug Administration | date=14 March 2008 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068TOC.cfm | access-date=13 November 2024 | archive-date=September 27, 2024 | archive-url=https://web.archive.org/web/20240927070756/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068TOC.cfm | url-status=dead }}{{cite web|title=Complete Nilotinib information from Drugs.com|work=Drugs.com|access-date=January 25, 2014|url=https://www.drugs.com/ppa/nilotinib.html|archive-date=February 1, 2014|archive-url=https://web.archive.org/web/20140201164347/http://www.drugs.com/ppa/nilotinib.html|url-status=live}} the European Union in November 2007,{{cite web|title=Tasigna : EPAR - Product Information|work=European Medicines Agency|publisher=Novartis Europharm Ltd.|date=October 18, 2013|access-date=January 25, 2014|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000798/WC500034394.pdf|archive-date=February 4, 2014|archive-url=https://web.archive.org/web/20140204012835/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000798/WC500034394.pdf|url-status=dead}} the Medicines and Healthcare products Regulatory Agency (MHRA) in January 2021, and the Therapeutic Goods Administration (TGA) in January 2008.{{cite web|title=Tasigna nilotinib|work=TGA eBusiness Services|publisher=October 21, 2013|access-date=January 25, 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00292-3|format=PDF|archive-date=April 6, 2017|archive-url=https://web.archive.org/web/20170406145845/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00292-3|url-status=live}}

There is weak evidence that nilotinib may be beneficial with Parkinson's disease (PD), with a small clinical trial suggesting it might halt progression and improve symptoms.{{cite journal | vauthors = Pagan F, Hebron M, Valadez EH, Torres-Yaghi Y, Huang X, Mills RR, Wilmarth BM, Howard H, Dunn C, Carlson A, Lawler A, Rogers SL, Falconer RA, Ahn J, Li Z, Moussa C | title = Nilotinib Effects in Parkinson's disease and Dementia with Lewy bodies | journal = Journal of Parkinson's Disease | volume = 6 | issue = 3 | pages = 503–517 | date = July 2016 | pmid = 27434297 | pmc = 5008228 | doi = 10.3233/JPD-160867 }} However, there were significant side effects including infection, liver function tests abnormalities, hallucinations and heart attack, and the benefit in PD disappeared at follow up after drug discontinuation, raising question as to whether it was truly a disease modifying therapy. Nilotinib is currently undergoing phase II studies for treatment of Parkinson's.{{cite journal | vauthors = Dash D, Goyal V | title = Anticancer Drugs for Parkinson's Disease: Is It a Ray of Hope or Only Hype? | journal = Annals of Indian Academy of Neurology | volume = 22 | issue = 1 | pages = 13–16 | year = 2019 | pmid = 30692753 | pmc = 6327695 | doi = 10.4103/aian.AIAN_177_18 | doi-access = free }} Scientists and medical professionals have advised caution with over-optimistic interpretation of its effects in Parkinson's due to the significant media hype surrounding the small and early clinical trial.{{cite journal | vauthors = Robledo I, Jankovic J | title = Media hype: Patient and scientific perspectives on misleading medical news | journal = Movement Disorders | volume = 32 | issue = 9 | pages = 1319–1323 | date = September 2017 | pmid = 28370445 | doi = 10.1002/mds.26993 | s2cid = 30022509 }}{{cite journal | vauthors = Wyse RK, Brundin P, Sherer TB | title = Nilotinib - Differentiating the Hope from the Hype | journal = Journal of Parkinson's Disease | volume = 6 | issue = 3 | pages = 519–522 | date = July 2016 | pmid = 27434298 | pmc = 5044778 | doi = 10.3233/JPD-160904 }} Dystonia and cognitive impairment have also been reported as side effects.{{cite journal | vauthors = Dash D, Goyal V | title = Anticancer Drugs for Parkinson's Disease: Is It a Ray of Hope or Only Hype? | journal = Annals of Indian Academy of Neurology | volume = 22 | issue = 1 | pages = 13–16 | date = 2019 | pmid = 30692753 | pmc = 6327695 | doi = 10.4103/aian.AIAN_177_18 | doi-access = free }}

Novartis announced in April 2011, that it was discontinuing a phase III trial of nilotinib as 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.{{Cite web | url=http://www.novartis.com/newsroom/media-releases/en/2011/1504991.shtml | title=Global Novartis News Archive | access-date=February 18, 2014 | archive-date=February 22, 2014 | archive-url=https://web.archive.org/web/20140222033323/http://www.novartis.com/newsroom/media-releases/en/2011/1504991.shtml | url-status=dead }}

Low dose nilotinib is also being investigated for use in Alzheimer's disease, as well as for ALS, dementia and Huntington's disease.{{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|access-date=April 11, 2017|date=May 10, 2013|archive-date=April 11, 2017|archive-url=https://web.archive.org/web/20170411220746/https://medicalxpress.com/news/2013-05-cancer-drug-build-up-toxic-brain.html|url-status=live}}

Nioltinib can be prepared as an amorphous solid distribution with resonant acoustic mixing in an attempt to avoid the interaction issues Tasigna has with food. Some work was done with 26 healthy volunteers, but a larger study has not been attempted.{{Cite patent|number=US20250032491A1|title=Amorphous nilotinib microparticles and uses thereof|gdate=2025-01-30|invent1=Wertz|invent2=Chen|invent3=McTarsney|inventor1-first=Christian F.|inventor2-first=Tzehaw|inventor3-first=Joseph|url=https://patents.google.com/patent/US20250032491A1}}

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