Nilotinib

Last updated

Nilotinib
Nilotinib2DACS.svg
Nilotinib3Dan.gif
Clinical data
Trade names Tasigna, others
Other namesAMN107
AHFS/Drugs.com Monograph
MedlinePlus a608002
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 30% [4]
Protein binding 98% [4]
Metabolism Liver (mostly CYP3A4-mediated) [4]
Elimination half-life 15-17 hours [4]
Excretion Faeces (93%) [4]
Identifiers
  • 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.166.395 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C28H22F3N7O
Molar mass 529.527 g·mol−1
3D model (JSmol)
  • 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) Yes check.svgY
  • Key:HHZIURLSWUIHRB-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Nilotinib, sold under the brand name Tasigna marketed worldwide by Novartis, is a medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome. [5] It may be used both in initial cases of chronic phase CML as well as in accelerated and chronic phase CML that has not responded to imatinib. [5] [6] It is taken by mouth. [6]

Contents

Common side effects may include low platelets, low white blood cells, anemia, rashes, vomiting, diarrhea, and joint pains. [6] Other serious side effects may include QT prolongation, sudden death, pancreatitis, and liver problems. [6] It is not safe for use during pregnancy. [6] Nilotinib is a Bcr-Abl tyrosine kinase inhibitor and works by interfering with signalling within the cancer cell. [6]

Nilotinib was approved for medical use in the United States in 2007. [6] It is on the World Health Organization's List of Essential Medicines. [7] It is approved as a generic medication. [8]

Medical uses

Nilotinib is used to treat Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia. [4]

Adverse effects

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. [9] 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. [10]

Nilotinib carries a black box warning in the United States for possible heart complications. [11] [2] Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance. [4] [12]

Cautions include: [4]

Dose reduction has been recommended in people with liver problems which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities. [13]

Hepatitis B virus reactivation may also occur. [14]

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. [13] Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3. [15]

It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors [16] will increase its action and inducers like St. John's wort [17] will decrease it. Patients report that pomegranates and starfruit may also interfere.

Pharmacology

Crystal structure of Abl kinase domain (blue) in complex with nilotinib (red) 3CS9 Abl1 Nilotinib.png
Crystal structure of Abl kinase domain (blue) in complex with nilotinib (red)

Nilotinib inhibits the kinases BCR-ABL, [18] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK. [19]

Structurally related to imatinib, [20] It is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells. [20] [21] [22] [23]

History

Nilotinib was developed by Novartis. [6] It was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance. [24] [21] [22]

Society and culture

It was approved for medical use by the FDA in October 2007, [9] EMA in September 2009, [25] MHRA in November 2007, [26] and TGA in January 2008. [12]

Research

Parkinson's disease

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. [27] 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. [28] 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. [29] [30] Dystonia and cognitive impairment have also been reported as side effects. [31]

Other

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. [32]

Low dose nilotinib is also being investigated for use in Alzheimer's disease, as well as for ALS, dementia and Huntington's disease. [33]

Related Research Articles

<span class="mw-page-title-main">Tyrosine kinase</span> Enzyme

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Philadelphia chromosome</span> Genetic abnormality in leukemia cancer cells

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signaling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

<span class="mw-page-title-main">Chronic myelogenous leukemia</span> Medical condition

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

<span class="mw-page-title-main">Imatinib</span> Chemical compound

Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome–positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.

<span class="mw-page-title-main">ABL (gene)</span> Human protein-coding gene on chromosome 9

Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene, which was initially isolated from the Abelson murine leukemia virus.

<span class="mw-page-title-main">Erlotinib</span> Medication for treatment of non-small-cell lung cancer

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Dasatinib</span> Chemical compound

Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+). It is taken by mouth.

<span class="mw-page-title-main">Vandetanib</span> Chemical compound

Vandetanib, sold under the brand name Caprelsa, is an anti-cancer medication that is used for the treatment of certain tumours of the thyroid gland. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor, the epidermal growth factor receptor, and the RET-tyrosine kinase. The drug was developed by AstraZeneca who later sold the rights to Sanofi in 2015.

Pazopanib, sold under the brand name Votrient, is an anti-cancer medication marketed worldwide by Novartis. It is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.

<span class="mw-page-title-main">Bosutinib</span> Chemical compound

Bosutinib, sold under the brand name Bosulif, is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.

<span class="mw-page-title-main">Nicholas Lydon</span> British biochemist

Nicholas B. Lydon FRS is a British scientist and entrepreneur. In 2009, he was awarded the Lasker Clinical Award and in 2012 the Japan Prize for the development of Gleevec, also known as Imatinib, a selective BCR-ABL inhibitor for the treatment of chronic myeloid leukaemia (CML), which converted a fatal cancer into a manageable chronic condition.

<span class="mw-page-title-main">Tyrosine kinase inhibitor</span> Drug typically used in cancer treatment

A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.

Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.

<span class="mw-page-title-main">Ponatinib</span> Medication

Ponatinib, sold under the brand name Iclusig, is a medication used for the treatment of chronic myeloid leukemia and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia. It was developed by Ariad Pharmaceuticals. It is a multi-targeted tyrosine-kinase inhibitor. Some forms of chronic myeloid leukemia, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.

<span class="mw-page-title-main">Canertinib</span> Chemical compound

Canertinib (CI-1033) is an experimental drug candidate for the treatment of cancer. It is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC50 0.8 nM), HER-2 (IC50 19 nM) and ErbB-4 (IC50 7 nM). By 2015, Pfizer had discontinued development of the drug.

<span class="mw-page-title-main">Radotinib</span> Chemical compound

Radotinib (INN; trade name Supect), and sometimes referred to by its investigational name IY5511, is a drug for the treatment of different types of cancer, most notably Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) with resistance or intolerance of other Bcr-Abl tyrosine-kinase inhibitors, such as patients resistant or intolerant to imatinib.

<span class="mw-page-title-main">Bafetinib</span> Chemical compound

Bafetinib (NS-187) is an experimental cancer drug developed by Nippon Shinyaku and licensed to CytRx. It is an inhibitor of Lyn and Bcr-Abl. It reached phase II clinical trials in 2010.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

<span class="mw-page-title-main">Asciminib</span> Chemical compound

Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukemia. Asciminib is a protein kinase inhibitor.

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved October 22, 2023.
  2. 1 2 "Tasigna- nilotinib capsule". DailyMed. February 8, 2024. Retrieved March 9, 2024.
  3. ↑ "Tasigna EPAR". European Medicines Agency (EMA). May 22, 2006. Retrieved August 27, 2024.
  4. 1 2 3 4 5 6 7 8 "Tasigna (nilotinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved January 25, 2014.
  5. 1 2 "Nilotinib". National Cancer Institute. February 1, 2008. Retrieved November 14, 2019.
  6. 1 2 3 4 5 6 7 8 "Nilotinib Monograph for Professionals". Drugs.com. Retrieved November 14, 2019.
  7. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ↑ "First-Time Generic Drug Approvals 2024". U.S. Food and Drug Administration (FDA). March 8, 2024. Retrieved March 9, 2024.
  9. 1 2 "Complete Nilotinib information from Drugs.com". Drugs.com. Retrieved January 25, 2014.
  10. ↑ Donatelli C, Chongnarungsin D, Ashton R (October 2014). "Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage". Leukemia & Lymphoma. 55 (10): 2408–2409. doi:10.3109/10428194.2014.887714. PMID   24467220. S2CID   43118790.
  11. ↑ "FDA Approves Tasigna for Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia". U.S. Food and Drug Administration. October 30, 2007. Retrieved August 4, 2009.
  12. 1 2 "Tasigna nilotinib" (PDF). TGA eBusiness Services. October 21, 2013. Retrieved January 25, 2014.
  13. 1 2 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 Metabolism and Drug Interactions. 29 (3): 179–190. doi:10.1515/dmdi-2013-0062. PMC   4407685 . PMID   24643910.
  14. ↑ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 960. ISBN   978-0-85711-338-2.
  15. ↑ Khurana V, Minocha M, Pal D, Mitra AK (May 2014). "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions. 29 (4): 249–259. doi:10.1515/dmdi-2014-0014. PMC   4407688 . PMID   24807167.
  16. ↑ Bailey DG, Malcolm J, Arnold O, Spence JD (August 1998). "Grapefruit juice-drug interactions". British Journal of Clinical Pharmacology. 46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x. PMC   1873672 . PMID   9723817.
  17. ↑ Komoroski BJ, Zhang S, Cai H, Hutzler JM, Frye R, Tracy TS, et al. (May 2004). "Induction and inhibition of cytochromes P450 by the St. John's wort constituent hyperforin in human hepatocyte cultures". Drug Metabolism and Disposition. 32 (5): 512–518. doi:10.1124/dmd.32.5.512. PMID   15100173.
  18. ↑ 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". British Journal of Cancer. 94 (12): 1765–1769. doi:10.1038/sj.bjc.6603170. PMC   2361347 . PMID   16721371.
  19. ↑ Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, et al. (March 2010). "Extended kinase profile and properties of the protein kinase inhibitor nilotinib". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1804 (3): 445–453. doi:10.1016/j.bbapap.2009.11.008. PMID   19922818.
  20. 1 2 Manley PW, Cowan-Jacob SW, Mestan J (December 2005). "Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1754 (1–2): 3–13. doi:10.1016/j.bbapap.2005.07.040. PMID   16172030.
  21. 1 2 Jabbour E, Cortes J, Kantarjian H (June 2010). "Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review". Core Evidence. 4: 207–213. doi: 10.2147/CE.S6003 . PMC   2899790 . PMID   20694077.
  22. 1 2 Olivieri A, Manzione L (June 2007). "Dasatinib: a new step in molecular target therapy". Annals of Oncology. 18 (Suppl 6): vi42–vi46. doi: 10.1093/annonc/mdm223 . PMID   17591830.
  23. ↑ Breccia M, Alimena G (February 2010). "Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia". Leukemia Research. 34 (2): 129–134. doi:10.1016/j.leukres.2009.08.031. PMID   19783301.
  24. ↑ Manley PW, Stiefl N, Cowan-Jacob SW, Kaufman S, Mestan J, Wartmann M, et al. (October 2010). "Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib". Bioorganic & Medicinal Chemistry. 18 (19): 6977–6986. doi:10.1016/j.bmc.2010.08.026. PMID   20817538.
  25. ↑ "Tasigna : EPAR - Product Information" (PDF). European Medicines Agency. Novartis Europharm Ltd. October 18, 2013. Archived from the original (PDF) on February 4, 2014. Retrieved January 25, 2014.
  26. ↑ "Tasigna 150mg Hard Capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Novartis Pharmaceuticals UK Ltd. September 9, 2013. Archived from the original on February 1, 2014. Retrieved January 25, 2014.
  27. ↑ Pagan F, Hebron M, Valadez EH, Torres-Yaghi Y, Huang X, Mills RR, et al. (July 2016). "Nilotinib Effects in Parkinson's disease and Dementia with Lewy bodies". Journal of Parkinson's Disease. 6 (3): 503–517. doi:10.3233/JPD-160867. PMC   5008228 . PMID   27434297.
  28. ↑ Dash D, Goyal V (2019). "Anticancer Drugs for Parkinson's Disease: Is It a Ray of Hope or Only Hype?". Annals of Indian Academy of Neurology. 22 (1): 13–16. doi: 10.4103/aian.AIAN_177_18 . PMC   6327695 . PMID   30692753.
  29. ↑ Robledo I, Jankovic J (September 2017). "Media hype: Patient and scientific perspectives on misleading medical news". Movement Disorders. 32 (9): 1319–1323. doi:10.1002/mds.26993. PMID   28370445. S2CID   30022509.
  30. ↑ Wyse RK, Brundin P, Sherer TB (July 2016). "Nilotinib - Differentiating the Hope from the Hype". Journal of Parkinson's Disease. 6 (3): 519–522. doi:10.3233/JPD-160904. PMC   5044778 . PMID   27434298.
  31. ↑ Dash D, Goyal V (2019). "Anticancer Drugs for Parkinson's Disease: Is It a Ray of Hope or Only Hype?". Annals of Indian Academy of Neurology. 22 (1): 13–16. doi: 10.4103/aian.AIAN_177_18 . PMC   6327695 . PMID   30692753.
  32. ↑ "Global Novartis News Archive". Archived from the original on February 22, 2014. Retrieved February 18, 2014.
  33. ↑ "Cancer drug prevents build-up of toxic brain protein". MedicalXpress.com. May 10, 2013. Retrieved April 11, 2017.
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