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
Drug class Antineoplastic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 30% [6]
Protein binding 98% [6]
Metabolism Liver (mostly CYP3A4-mediated) [6]
Elimination half-life 15-17 hours [6]
Excretion Faeces (93%) [6]
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 among others, is a anti-cancer medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome. [3] [7] 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. [3] [7] [8] It is taken by mouth. [3] [8]

Contents

Common side effects may include low platelets, low white blood cells, anemia, rashes, vomiting, diarrhea, and joint pains. [8] Other serious side effects may include QT prolongation, sudden death, pancreatitis, and liver problems. [8] It is not safe for use during pregnancy. [8] Nilotinib is a Bcr-Abl tyrosine kinase inhibitor and works by interfering with signalling within the cancer cell. [3] [8]

Nilotinib was approved for medical use in the United States in 2007. [3] [8] It is on the World Health Organization's List of Essential Medicines. [9] It is approved as a generic medication. [10]

Medical uses

Nilotinib is used to treat Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia. [3] [6] It is indicated for the treatment of newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase; [3] [5] adults with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia resistant to or intolerant to prior therapy that included imatinib; [3] [5] and children with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia resistant or intolerant to prior tyrosine-kinase inhibitor therapy. [3] [5]

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. [11] 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. [12]

Nilotinib carries a black box warning in the United States for possible heart complications. [3] [13] Contraindications include long QT syndrome, hypokalaemia, hypomagnesaemia, pregnancy, planned pregnancy, lactation and galactose/lactose intolerance. [6] [14]

Cautions include: [6]

Dose reduction has been recommended in people with liver problems which involves recommendation of lower starting dose and monitoring of any hepatic function abnormalities. [15]

Hepatitis B virus reactivation may also occur. [16]

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. [15] Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3. [17]

It is a substrate for CYP3A4 and hence grapefruit juice and other CYP3A4 inhibitors [18] will increase its action and inducers like St. John's wort [19] 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, [20] KIT, LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK. [21]

Structurally related to imatinib, [22] It is 10–30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells. [22] [23] [24] [25]

History

Nilotinib was developed by Novartis. [8] It was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance. [26] [23] [24]

Society and culture

It was approved for medical use by the US Food and Drug Administration (FDA) in October 2007, [27] [11] the European Union in November 2007, [5] [28] the Medicines and Healthcare products Regulatory Agency (MHRA) in January 2021, [1] and the Therapeutic Goods Administration (TGA) in January 2008. [14]

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. [29] 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. [30] 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. [31] [32] Dystonia and cognitive impairment have also been reported as side effects. [33]

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. [34]

Low dose nilotinib is also being investigated for use in Alzheimer's disease, as well as for ALS, dementia and Huntington's disease. [35]

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">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.

K562 cells were the first human immortalised myelogenous leukemia cell line to be established. K562 cells are of the erythroleukemia type, and the cell line is derived from a 53-year-old female chronic myelogenous leukemia patient in blast crisis. The cells are non-adherent and rounded, are positive for the bcr:abl fusion gene, and bear some proteomic resemblance to both undifferentiated granulocytes and erythrocytes.

<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">BCR (gene)</span> Protein domain

The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL fusion protein, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">Acute myeloblastic leukemia with maturation</span> Medical condition

Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).

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

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

<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">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

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  2. ↑ "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.
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  4. ↑ "Danziten- nilotinib tablet". DailyMed. November 1, 2024. Retrieved December 23, 2024.
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  9. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
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  12. ↑ 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.
  13. ↑ "FDA Approves Tasigna for Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia". U.S. Food and Drug Administration. October 30, 2007. Archived from the original on August 27, 2009. Retrieved August 4, 2009.
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  18. ↑ 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.
  19. ↑ 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.
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  21. ↑ 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.
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  25. ↑ 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.
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  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
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