Drug
nilotinib

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PharmGKB annotates drug labels containing pharmacogenetic information approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), the Pharmaceuticals and Medical Devices Agency, Japan (PMDA), and Health Canada (Santé Canada) (HCSC). PharmGKB annotations provide a brief summary of the PGx in the label, an excerpt from the label and a downloadable highlighted label PDF file. A list of genes and phenotypes found within the label is mapped to label section headers and listed at the end of each annotation. PharmGKB also attempts to interpret the level of action implied in each label with the "PGx Level" tag.

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last updated 10/25/2013

FDA Label for nilotinib and ABL1, BCR, UGT1A1

Genetic testing required

Summary

Nilotinib is indicated for use in patients diagnosed with Philadelphia chromosome positive (presence of a BCR-ABL1 gene fusion) chronic myeloid leukemia, due to its mechanism of action. Individuals with the UGT1A1*28 genotype (TA)7/(TA)7 (rs8175347) are at an increased risk of hyperbilirubinemia when taking nilotinib (testing is not required for UGT1A1).

There's more of this label. Read more.


last updated 10/27/2013

European Medicines Agency (EMA) Label for nilotinib and ABL1, BCR

Genetic testing required

Summary

The EMA European Public Assessment Report (EPAR) for nilotinib (Tasigna) states it is indicated for patients who have Philadelphia chromosome-positive (presence of a BCR-ABL1 gene fusion) chronic myelogenous leukemia (CML). The label differs from that of the FDA as it does not contain any information regarding UGT1A1 genotype.

There's more of this label. Read more.


last updated 06/08/2015

Health Canada Santé Canada (HCSC) Label for nilotinib and ABI1, BCR, UGT1A1

Genetic testing required

Summary

The product monograph for nilotinib (TASIGNA) states that it is indicated for patients with Philadelphia chromosome positive (BCR-ABL1 fusion) chronic myeloid leukemia, though individuals with the BCR-ABL T315I mutation are highly resistant to the drug. The monograph also notes that patients homozygous for the UGT1A1*28 allele (rs8175347; (TA)7) may be at risk for hyperbilirubinemia when receiving nilotinib.

There's more of this label. Read more.


PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

List of all variant annotations for nilotinib

Gene ? Variant?
(144)
Alternate Names ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA
rs1061018 13590574A>G, 42159T>C, 623T>C, 89042853A>G, Phe208Ser
A > G
Missense
Phe208Ser
No VIP available CA VA
rs2231137 13608835C>T, 23898G>A, 34G>A, 89061114C>T, ABCG2:V12M, Val12Met
C > T
Missense
Val12Met
No VIP available No Clinical Annotations available VA
rs2231142 13600044G>T, 32689C>A, 421C>A, 89052323G>T, ABCG2: Q141K, ABCG2:421C>A, ABCG2:Q141K, ABCG2:c.421C>A, Gln141Lys, rs2231142
G > T
Missense
Gln141Lys
No VIP available CA VA
rs41282401 13583887C>G, 48846G>C, 886G>C, 89036166C>G, Asp296His
C > G
Missense
Asp296His
No VIP available No Clinical Annotations available VA
rs58818712 13566399A>C, 1574T>G, 66334T>G, 89018678A>C, Leu525Arg
A > C
Missense
Leu525Arg
No VIP available CA VA
rs8175347 233760235_233760236TA[5][6][7][8], 5-TA insertion in promoter, 7-TA insertion in promoter, 8-TA insertion in promoter, UGT1A1*28, UGT1A1*36, UGT1A1*37, microsatellite, short tandem repeat
(TA)6 > (TA)8
(TA)6 > (TA)5
(TA)6 > (TA)7
Not Available
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 144
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • amn-107
  • amn107
Trade Names
  • Tasigna
  • Tasigna (Novartis)
Brand Mixture Names

PharmGKB Accession Id:
PA165958345
Type(s):
Drug

Description

Nilotinib, also known as AMN107, is a tyrosine kinase inhibitor under investigation as a possible treatment for chronic myelogenous leukemia (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 (Gleevec R ), another tyrosine kinase inhibitor currently used as a first-line treatment. Wikipedia

Source: Drug Bank

Indication

For the potential treatment of various leukemias, including chronic myeloid leukemia (CML).

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Chronic myelogenous leukaemia (CML) is caused by the BCR-ABL oncogene. Nilotinib inhibits the tyrosine kinase activity of the BCR-ABL protein. Nilotinib fits into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib, over-riding resistance caused by mutations. The ability of AMN107 to inhibit TEL-platelet-derived growth factor receptor-beta (TEL-PDGFRbeta), which causes chronic myelomonocytic leukaemia, and FIP1-like-1-PDGFRalpha, which causes hypereosinophilic syndrome, suggests potential use of AMN107 for myeloproliferative diseases characterised by these kinase fusions (Stover et al, 2005; Weisberg et al, 2005). AMN107 also inhibits the c-Kit receptor kinase, including the D816V-mutated variant of KIT, at pharmacologically achievable concentrations, supporting potential utility in the treatment of mastocytosis, and gastrointestinal stromal tumours (Weisberg et al, 2005; von Bubnoff et al, 2005; Gleixner et al, 2006).

Source: Drug Bank

Pharmacology

Nilotinib is a transduction inhibitor that targets BCR-ABL, c-kit and PDGF, for the potential treatment of various leukemias, including chronic myeloid leukemia (CML).

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Absorption

Orally available

Source: Drug Bank

Half-Life

15 hours

Source: Drug Bank

Chemical Properties

Chemical Formula

C28H22F3N7O

Source: Drug Bank

Isomeric SMILES

Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)C(=O)Nc4cc(cc(c4)n5cc(nc5)C)C(F)(F)F

Source: Drug Bank

Canonical SMILES

CC1=CN(C=N1)C1=CC(=CC(NC(=O)C2=CC(NC3=NC=CC(=N3)C3=CN=CC=C3)=C(C)C=C2)=C1)C(F)(F)F

Source: Drug Bank

Average Molecular Weight

529.5158

Source: Drug Bank

Monoisotopic Molecular Weight

529.183792976

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Interactions

Drug Description
nilotinib May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated. (source: Drug Bank)
nilotinib Nilotinib may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy. (source: Drug Bank)
nilotinib Nilotinib may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy. (source: Drug Bank)
nilotinib Nilotinib, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Nilotinib is initiated, discontinued, or dose changed. (source: Drug Bank)
nilotinib Nilotinib, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Nilotinib is initiated, discontinued, or dose changed. (source: Drug Bank)
nilotinib Telithromycin may reduce clearance of Nilotinib. Concomitant therapy should be avoided. (source: Drug Bank)
nilotinib May cause additive QTc-prolonging effects. Concomitant therapy should be avoided. (source: Drug Bank)
nilotinib May cause additive QTc-prolonging effects. Concomitant therapy should be avoided. (source: Drug Bank)
nilotinib The p-glycoprotein inhibitor, Nilotinib, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
nilotinib May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated. (source: Drug Bank)
nilotinib Nilotinib may decrease the effect of Tramadol by decreasing active metabolite production. (source: Drug Bank)
nilotinib Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events. (source: Drug Bank)
nilotinib The moderate CYP2C8 inhibitor, Nilotinib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Nilotinib is initiated, discontinued to dose changed. (source: Drug Bank)
nilotinib May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated. (source: Drug Bank)
nilotinib Voriconazole may increase the serum concentration of nilotinib by inhibiting its metabolism by CYP3A4. Additive QTc prolongation may also occur. Concomitant therapy should be avoided. (source: Drug Bank)
nilotinib Additive QTc prolongation may occur. Concomitant therapy should be avoided. (source: Drug Bank)
nilotinib Additive QTc-prolongation may occur. Concomitant therapy should be avoided. (source: Drug Bank)
nilotinib Additive QTc-prolonging effects increases risk of cardiac arrhythmias. Concomitant therapy should be avoided. (source: Drug Bank)

Curated Information ?

Publications related to nilotinib: 9

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Interaction of the Efflux Transporters ABCB1 and ABCG2 With Imatinib, Nilotinib, and Dasatinib. Clinical pharmacology and therapeutics. 2014. Eadie L N, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line. Pharmacogenetics and genomics. 2014. Skoglund Karin, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Challenges in pharmacogenetics. European journal of clinical pharmacology. 2013. Cascorbi Ingolf, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. International journal of clinical oncology. 2013. Shibata Takashi, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Playing Russian Roulette With Tyrosine Kinase Inhibitors. Clinical pharmacology and therapeutics. 2012. Szmulewitz R Z, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2). BMC structural biology. 2009. Winger Jonathan A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Nilotinib: a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Clinical therapeutics. 2008. Deremer David L, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2007. Singer J B, et al. PubMed

LinkOuts

DrugBank:
DB04868
ChEBI:
52172
PubChem Compound:
644241
PubChem Substance:
99443226
ChemSpider:
559260

Clinical Trials

These are trials that mention nilotinib and are related to either pharmacogenetics or pharmacogenomics.

No trials found.

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.