Lapatinib

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Lapatinib
250px
250px
Systematic (IUPAC) name
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-
[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]
quinazolin-4-amine
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]
Pregnancy
category
  • D
Routes of
administration		 Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability Variable, increased with food
Protein binding >99%
Metabolism Hepatic, mostly CYP3A-mediated (minor 2C19 and 2C8 involvement)
Biological half-life 24 hours
Excretion Mostly fecal
Identifiers
CAS Number 231277-92-2
388082-78-8 (ditosylate)
ATC code L01XE07 (WHO)
PubChem CID 208908
DrugBank DB01259
ChemSpider 181006
Chemical data
Formula C29H26ClFN4O4S
Molar mass 581.058 g/mol[[Script error: No such module "String".]]
Script error: No such module "TemplatePar".Expression error: Unexpected < operator.

Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours.[1] It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway.[2] It is used in combination therapy for HER2-positive breast cancer. It has been approved as front-line therapy in triple positive breast cancer and as an adjuvant therapy when patients have progressed on Herceptin.[3]

Status

On March 13, 2007, the U.S. Food and Drug Administration (FDA) approved lapatinib in combination therapy for breast cancer patients already using capecitabine (Xeloda, Roche).[3][2] In February of 2010, Tykerb received accelerated approval as front-line therapy in triple positive breast cancer.[4]

Pharmaceutical company GlaxoSmithKline (GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe).[5] The drug currently has approval for sale and clinical use in the US,[2][5] Australia,[2] Bahrain,[2] Israel, Kuwait,[2] Venezuela,[2] Brazil,[6] New Zealand,[6][7] South Korea,[6] Switzerland,[5] Japan, the European Union, India and Pakistan [5].

Mode of action

Biochemistry

Lapatinib inhibits the tyrosine kinase activity associated with two oncogenes, EGFR (epidermal growth factor receptor) and HER2/neu (Human EGFR type 2)[8]. Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women.[2] Like Sorafenib, lapatinib is a protein kinase inhibitor shown to decrease tumor-causing breast cancer stem cells. [9] Lapatinib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFR/HER2 protein kinase domain, preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinase#Signal transduction).[10]

Clinical application

Lapatinib is used as a treatment for women's breast cancer in treatment naive, ER+/EGFR+/HER2+ breast cancer patients (now often called "triple positive") and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as anthracycline, taxane-derived drugs, or trastuzumab (Herceptin, Genentech).

A 2006 GSK-supported randomized clinical trial on female breast cancer previously being treated with those agents (anthracycline, a taxane and trastuzumab) demonstrated that administrating lapatinib in combination with capecitabine delayed the time of further cancer growth compared to regime that use capecitabine alone. The study also reported that risk of disease progression was reduced by 51%, and that the combination therapy was not associated with increases in toxic side effects.[11] The outcome of this study resulted in a somewhat complex and rather specific initial indication for lapatinib—use only in combination with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab.

In February of 2010, based on recent studies[12], GSK issued a press release announcing the approval of lapatinib in first-line therapy in triple positive (hormone receptor, EGFR, HER2) breast cancer patients.[4]

Adverse effects

Like many small molecule tyrosine kinase inhibitors, lapatinib is regarded as well tolerated. The most common side effects reported are diarrhea, fatigue, nausea and rashes.[2][13] In ongoing studies the drug have shown to provoke toxic hepatitis, the toxicity is reversible when the treatment is stopped.[citation needed]

References

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External links

CI monoclonal antibodies ("-mab")
Others for solid tumors
Tyrosine kinase inhibitors ("-nib")
Other
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  1. ↑ Burris HA (2004). "Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib". Oncologist. 9 Suppl 3: 10–5. doi:10.1634/theoncologist.9-suppl_3-10. PMID 15163842. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  3. ↑ 3.0 3.1 "FDA Approves Advanced Breast Cancer Drug". NewsMax.com Wires. Washington: Associated Press. 2007-03-13. Retrieved 2008-09-25. 
  4. ↑ 4.0 4.1 Company Press Release, Feb 1, 2010: GSK’s TYKERB® receives accelerated approval for first-line combination treatment of hormone receptor positive, HER2+/ErbB2+ metastatic breast cancer
  5. ↑ 5.0 5.1 5.2 5.3 "GlaxoSmithKline receives marketing authorisation in the EU for Tyverb (lapatinib), the first oral targeted therapy for ErbB2-positive breast cancer" (Press release). GlaxoSmithKline. 2008-06-12. http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10063.htm. Retrieved 2008-06-21. 
  6. ↑ 6.0 6.1 6.2 "GlaxoSmithKline Reports Positive New Data On Tykerb (lapatinib) At The 2007 American Society Of Clinical Oncology (ASCO) Annual Meeting" (Press release). Medical News Today. June 4, 2007. http://www.medicalnewstoday.com/articles/72987.php.  Retrieved December 2, 2008.
  7. ↑ "Data Sheet: TYKERB". Medsafe. New Zealand Medicines and Medical Devices Safety Authority. March 12, 2008.  Retrieved December 2, 2008.
  8. ↑ Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. PMID: 15374980
  9. ↑ Dr. Angel Rodriguez (April 2008). "New type of drug shrinks primary breast cancer tumors significantly in just six weeks; research provides leads to a new target in cancer treatment – the cancer stem cell". http://www.ecco-org.eu/News/Press-room/Press-release/page.aspx/439?xf_itemId=265&xf_catId=27. 
  10. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  11. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  12. ↑ Johnston, S et al. Lapatinib combined with letrozole vs letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.”J Clin Oncol 2009 27:5538-5546
  13. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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