Drug/Small Molecule:
lapatinib

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 lapatinib and ERBB2

This label is on the FDA Biomarker List
Genetic testing required

Summary

TYKERB (lapatinib) is "indicated in combination with: 1) capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2(ERBB2) and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. 2)letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated." HER2(ERBB2) status should be determined prior to the use of lapatinib.

Annotation

Excerpt from the lapatinib drug label:

TYKERB, a kinase inhibitor, is indicated in combination with:
-capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.
-letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.

The recommended dose of TYKERB for hormone receptor positive, HER2 positive metastatic breast cancer is 1500 mg (6 tablets) given orally once daily continuously in combination with letrozole. When TYKERB is coadministered with letrozole, the recommended dose of letrozole is 2.5 mg once daily.

TYKERB is likely to increase exposure to concomitantly administered drugs which are substrates of CYP3A4, CYP2C8, or P-glycoprotein (ABCB1). Avoid strong CYP3A4 inhibitors. If unavoidable, consider dose reduction of TYKERB in patients coadministered a strong CYP3A4 inhibitor. (2.2, 7.2).
Avoid strong CYP3A4 inducers. If unavoidable, consider gradual dose increase of TYKERB in patients coadministered a strong CYP3A4 inducer.

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR (ErbB1)) and of Human Epidermal Receptor Type 2 (HER2 (ErbB2)) receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a dissociation half-life of >=300 minutes. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.

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

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

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Breast Neoplasms
    • Indications & usage section, Adverse reactions section
    • source: PHONT
  • Carcinoma, Non-Small-Cell Lung
    • Indications & usage section, Warnings section, Adverse reactions section
    • source: PHONT
  • Neoplasms
    • Indications & usage section, Warnings section, Adverse reactions section
    • source: PHONT
  • CYP3A4
    • Drug interactions section, Clinical pharmacology section, metabolism/PK
    • source: FDA Label
  • ERBB2
    • Indications & usage section, Clinical pharmacology section, efficacy
    • source: FDA Label

last updated 10/27/2013

European Medicines Agency (EMA) Label for lapatinib and ERBB2, HLA-DQA1, HLA-DRB1

Genetic testing required

Summary

The EMA European Public Assessment Report (EPAR) for lapatinib (Tyverb) contains pharmacogenetic information regarding the indication of the drug in HER2+ (ERBB2) breast cancer, and that HER2 status should be determined using an accurate technique. It also contains pharmacogenetic information regarding an increased risk of drug-induced hepatotoxicity in patients carrying the DQA1*02:01 or DRB1*07:01 HLA alleles.

Annotation

Excerpts from the lapatinib (Tyverb) EPAR:

Tyverb is indicated for the treatment of patients with breast cancer, whose tumours overexpress HER2 (ErbB2).


Lapatinib inhibits ErbB-driven tumour cell growth in vitro and in various animal models.


HER2 (ErbB2) overexpressing tumours are defined by IHC3+, or IHC2+ with gene amplification or gene amplification alone. HER2 status should be determined using accurate and validated methods.


Patients who carry the HLA alleles DQA1*02:01 and DRB1*07:01 have increased risk of Tyverb-associated hepatotoxicity. In a large, randomised clinical trial of Tyverb monotherapy (n=1,194), the cumulative frequency of severe liver injury (ALT >5 times the upper limit of normal, NCI CTCAE grade 3) at 1 year of treatment was 2.8% overall.

This information is highlighted in the following sections:
Therapeutic indications, posology and method of administration, special warnings and precautions for use, package leaflet: information for the user.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the lapatinib (Tyverb) 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.

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?

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
rs9344 *1365+4648C>T, 12038G>A, 14768705G>A, 69462910G>A, 723G>A, CCND1 (A870G), CCND1:870G>A, Pro241=, rs603965
G > A
Intronic
Pro241Pro
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • FMM
  • GW 572016
  • GW572016
  • Lapatinib ditosylate
  • Lapatinib tosilate hydrate
  • lapatinib
Trade Names
  • Tycerb
  • Tykerb
Brand Mixture Names

PharmGKB Accession Id:
PA152241907

Description

Lapatinib is an anti-cancer drug developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug Capecitabine. Lapatinib is human epidermal growth factor receptor type 2 (HER2/ERBB2) and epidermal growth factor receptor (HER1/EGFR/ERBB1) tyrosine kinases inhibitor. It binds to the intracellular phosphorylation domain to prevent receptor autophosphorylation upon ligand binding.

Source: Drug Bank

Indication

Indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal receptor type 2 (HER2) protein and who have received prior therapy including an anthracycline, a taxane, and trastuzuma.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2)with a dissociation half-life of >=300 minutes. Lapatinib inhibits ERBB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when lapatinib and 5-florouracil (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents.

Source: Drug Bank

Pharmacology

Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. An anti-cancer drug, lapatinib was developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug capecitabine.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.

Source: Drug Bank

Protein Binding

Highly bound (>99%) to albumin and alpha-1 acid glycoprotein

Source: Drug Bank

Absorption

Absorption following oral administration of lapatinib is incomplete and variable.

Source: Drug Bank

Half-Life

Single-dose terminal half life: 14.2 hours
Effective multiple-dose half life: 24 hours

Source: Drug Bank

Toxicity

There has been a report of one patient who took 3,000 mg of lapatinib for 10 days. This patient had grade 3 diarrhea and vomiting on day 10.

Source: Drug Bank

Route of Elimination

Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.

Source: Drug Bank

Chemical Properties

Chemical Formula

C29H26ClFN4O4S

Source: Drug Bank

Isomeric SMILES

CS(=O)(=O)CCNCc1ccc(o1)c2ccc3c(c2)c(ncn3)Nc4ccc(c(c4)Cl)OCc5cccc(c5)F

Source: OpenEye

Canonical SMILES

CS(=O)(=O)CCNCC1=CC=C(O1)C1=CC2=C(C=C1)N=CN=C2NC1=CC(Cl)=C(OCC2=CC(F)=CC=C2)C=C1

Source: Drug Bank

Average Molecular Weight

581.058

Source: Drug Bank

Monoisotopic Molecular Weight

580.134731942

Source: Drug Bank

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. EGFR Inhibitor Pathway, Pharmacodynamics
    Model non-tissue specific cancer cell displaying genes that may be involved in the treatment using epidermal growth factor receptor specific tyrosine kinase inhibitors or monoclonal antibodies.

External Pathways

Links to non-PharmGKB pathways.

PharmGKB contains no links to external pathways for this drug. To report a pathway, click here.

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 Targets

Gene Description
EGFR (source: Drug Bank)
ERBB2 (source: Drug Bank)

Drug Interactions

Drug Description
lapatinib Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. (source: Drug Bank)
lapatinib Lapatinib, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Lapatinib is initiated, discontinued, or dose changed. (source: Drug Bank)
lapatinib Lapatinib, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Lapatinib is initiated, discontinued, or dose changed. (source: Drug Bank)
lapatinib Telithromycin may reduce clearance of Lapatinib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Lapatinib if Telithromycin is initiated, discontinued or dose changed. (source: Drug Bank)
lapatinib May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration. (source: Drug Bank)
lapatinib May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration. (source: Drug Bank)
lapatinib Lapatinib may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity. (source: Drug Bank)
lapatinib Lapatinib may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity. (source: Drug Bank)
lapatinib The p-glycoprotein inhibitor, Lapatinib, 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)
lapatinib Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration. (source: Drug Bank)
lapatinib Lapatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. (source: Drug Bank)
lapatinib The CYP3A4 inhibitor, Lapatinib, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Lapatinib is initiated, discontinued or dose changed. (source: Drug Bank)
lapatinib The CYP3A4 inhibitor, Lapatinib, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Lapatinib is initiated, discontinued or dose changed. (source: Drug Bank)
lapatinib The moderate CYP2C8 inhibitor, Lapatinib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Lapatinib is initiated, discontinued to dose changed. (source: Drug Bank)
lapatinib Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. (source: Drug Bank)
lapatinib Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of lapatinib by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lapatinib if voriconazole is initiated, discontinued or dose changed. (source: Drug Bank)
lapatinib Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP). (source: Drug Bank)
lapatinib Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated. (source: Drug Bank)
lapatinib Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP). (source: Drug Bank)

Curated Information ?

Publications related to lapatinib: 15

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Emerging landscape of oncogenic signatures across human cancers. Nature genetics. 2013. Ciriello Giovanni, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
PharmGKB summary: very important pharmacogene information for the epidermal growth factor receptor. Pharmacogenetics and genomics. 2013. Hodoglugil Ugur, 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
Predictive Genetic Testing for Drug-Induced Liver Injury: Considerations of Clinical Utility. Clinical pharmacology and therapeutics. 2012. Alfirevic A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2012. Labonte M J, 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
Lapatinib-induced liver injury characterized by class II HLA and Gilbert's syndrome genotypes. Clinical pharmacology and therapeutics. 2012. Spraggs C F, 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
Positive interaction between lapatinib and capecitabine in human breast cancer models: study of molecular determinants. Fundamental & clinical pharmacology. 2011. Chefrour Mohamed, 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
Pharmacogenomic contribution to drug response. Cancer journal (Sudbury, Mass.). 2011. Watson Roshawn G, 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
Targeted cancer therapies in the twenty-first century: lessons from imatinib. Clinical pharmacology and therapeutics. 2010. Stegmeier F, 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 dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38. International journal of cancer. Journal international du cancer. 2009. LaBonte Melissa J, 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
Grb7 upregulation is a molecular adaptation to HER2 signaling inhibition due to removal of Akt-mediated gene repression. PloS one. 2010. Nencioni Alessio, 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
Evolving novel anti-HER2 strategies. The lancet oncology. 2009. Jones Kellie L, 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
Beyond trastuzumab: overcoming resistance to targeted HER-2 therapy in breast cancer. Current cancer drug targets. 2009. Bedard Philippe L, 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
MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, N.Y.). 2007. Engelman Jeffrey A, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0173-0752-00
DrugBank:
DB01259
PDB:
FMM
ChEBI:
49603
KEGG Drug:
D04024
PubChem Compound:
208908
PubChem Substance:
14911387
46507141
BindingDB:
5445
ChemSpider:
181006
HET:
FMM
Therapeutic Targets Database:
DCL000344
FDA Drug Label at DailyMed:
63319b01-cad6-4d0a-c39b-938fa951a808

Clinical Trials

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

Common Searches

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