Drug/Small Molecule:
nilotinib

PharmGKB contains no dosing guidelines for this drug/small molecule. To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.



last updated 10/25/2013

FDA Label for nilotinib and ABL1, BCR, UGT1A1

This label is on the FDA Biomarker List
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).

Annotation

Nilotinib (Tasigna) is indicated for use in patients diagnosed with Philadelphia chromosome positive chronic myeloid leukemia (BCR-ABL1 gene fusion) due to its mechanism of action as a BCR-ABL1 kinase inhibitor. The FDA-approved drug label includes recommended dosing guidelines for newly diagnosed individuals and for those resistant or intolerant to previous treatments.

The drug label for nilotinib also contains information regarding UGT1A1 genotype. Nilotinib is an inhibitor of UGT1A1 in vitro, and individuals with the UGT1A1*28 genotype (TA)7/(TA)7 (rs8175347) are at an increased risk of hyperbilirubinemia when taking nilotinib.

The drug can also inhibit ABCB1, and can inhibit or induce numerous CYP enzymes, thus may affect the pharmacokinetics of drugs taken concomitantly (as discussed in section 7.1). The label also states that CYP3A4 inhibitors or inducers should be avoided when taking nilotinib due to the possible effect on nilotinib pharmacokinetics and efficacy.

Excerpts from the nilotinib drug label:

Tasigna is a kinase inhibitor indicated for:
The treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The study is ongoing and further data will be required to determine long-term outcome.
The treatment of chronic phase (CP) and accelerated phase (AP) Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib.


Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. In vitro, nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML.


Tasigna can increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during Tasigna treatment. In this study, the (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients (see Warnings and Precautions (5.5)).

For the complete drug label text with sections containing this pharmacogenetic information highlighted, see the Nilotinib drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
    • Indications & usage section, Dosage & administration section, Information for patients section, Clinical pharmacology section, Clinical studies section, Mechanism of action section, Use in specific populations section
    • source: FDA Label
  • ABCB1
    • Drug interactions section, metabolism/PK
    • source: FDA Label
  • ABL1
    • Clinical pharmacology section, Clinical studies section, Mechanism of action section, efficacy
    • source: FDA Label
  • BCR
    • Clinical pharmacology section, Clinical studies section, Mechanism of action section, efficacy
    • source: FDA Label
  • CYP3A4
    • Dosage & administration section, Warnings section, Drug interactions section, Information for patients section, Warnings and precautions section, metabolism/PK
    • source: FDA Label
  • UGT1A1
    • Drug interactions section, Clinical pharmacology section, efficacy
    • source: FDA Label

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.

Annotation

The label also contains information regarding avoiding use of CYP3A4 inhibitors which may reduce exposure to the drug as the drug is primarily metabolized by CYP3A4. The drug is also a substrate of ABCB1 (P-gp).

Excerpts from the nilotinib (Tasigna) EPAR:

Tasigna is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase.

Nilotinib is mainly metabolised in the liver and is also a substrate for the multi-drug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed nilotinib may be influenced by substances that affect CYP3A4 and/or P-gp.

This information is highlighted in the following sections:
Therapeutic indications, special warnings and precautions for use, interaction with other medicinal products and other forms of interaction. pharmacodynamic properties, pharmacokinetic properties and other forms of interaction, key elements to be included in the educational brochure, package leaflet: information for the user.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the nilotinib EMA drug label.

*Disclaimer: The contents of this page have not been endorsed by the EMA and are the sole responsibility of PharmGKB.


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.

? = Mouse-over for quick help

This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?
BCR-ABL Quantitation; ABL Kinase Domain Sequencing BCR-ABL (reciprocal translocation involving chromosomes 9 and 22, t(9,22)(q34, q11))

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.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No Clinical Annotations available VA
rs1061018 13590574A>G, 42159T>C, 623T>C, 89042853A>G, Phe208Ser
A > G
Missense
Phe208Ser
No VIP available No Clinical Annotations available 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 No Clinical Annotations available 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 138
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

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 No Clinical Annotation available 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.

Common Searches

Search PubMed
Search Medline Plus
Search PubChem
Search CTD

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