Lapatinib
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| Systematic (IUPAC) name | |
| N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6- [5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine |
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| Clinical data | |
| Trade names | Tykerb, Tyverb |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a607055 |
| Licence data | EMA:Link, US FDA:link |
| Pregnancy cat. | D |
| Legal status | Prescription Only (S4) (AU) ℞-only (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | Variable, increased with food |
| Protein binding | >99% |
| Metabolism | Hepatic, mostly CYP3A-mediated (minor 2C19 and 2C8 involvement) |
| Half-life | 24 hours |
| Excretion | Mostly fecal |
| Identifiers | |
| CAS number | 231277-92-2  388082-78-8 (ditosylate) |
| ATC code | L01XE07 |
| PubChem | CID 208908 |
| DrugBank | DB01259 |
| ChemSpider | 181006  |
| UNII | 0VUA21238F |
| KEGG | D04024 |
| ChEBI | CHEBI:49603 |
| ChEMBL | CHEMBL554 |
| Chemical data | |
| Formula | C29H26ClFN4O4S |
| Mol. mass | 581.058 g/mol |
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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/neu and epidermal growth factor receptor (EGFR) pathways.[2] It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).[3]
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Status [edit]
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).[2][3] In January 2010, Tykerb received accelerated approval for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated.[3]
Pharmaceutical company GlaxoSmithKline (GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe).[4] The drug currently has approval for sale and clinical use in the US,[2][4] Australia,[2] Bahrain,[2] Israel, Kuwait,[2] Venezuela,[2] Brazil,[5] New Zealand,[5][6] South Korea,[5] Switzerland,[4] Japan, the European Union, Lebanon, India and Pakistan.[4]
The drug lapatinib ditosylate is classified as S/NM (a synthetic compound showing competitive inhibition of the natural product) that is naturally derived or inspired substrate (Gordon M. Cragg, Paul G. Grothaus, and David J. Newman, Impact of Natural Products on Developing New Anti-Cancer Agents, Chem. Rev. 2009, 109, 3012–3043)
Mode of action [edit]
Biochemistry [edit]
Lapatinib inhibits the tyrosine kinase activity associated with two oncogenes, EGFR (epidermal growth factor receptor) and HER2/neu (Human EGFR type 2).[7] 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. [8] 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).[9]
Clinical application [edit]
Breast cancer [edit]
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 regimens 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.[10] 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.
Adverse effects [edit]
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][11] In ongoing studies the drug has been shown to provoke toxic hepatitis, the toxicity is reversible when the treatment is stopped.[citation needed]
References [edit]
- ^ 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.
- ^ a b c d e f g h i Higa GM & Abraham J (September 2007). "Lapatinib in the treatment of breast cancer" (log in required). Expert Review of Anticancer Therapy (Future Drugs) 7 (9): 1183–92. doi:10.1586/14737140.7.9.1183. PMID 17892419.
- ^ a b c Pazdur, Richard (14 January 2011). "FDA Approval for Lapatinib Ditosylate". Cancer.gov.
- ^ a b c d "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. Retrieved 2008-06-21.
- ^ a b c "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. Retrieved December 2, 2008.
- ^ "Data Sheet: TYKERB". Medsafe. New Zealand Medicines and Medical Devices Safety Authority. March 12, 2008. Retrieved December 2, 2008.
- ^ Wood, ER, Truesdale, AT, McDonald, OB, Yuan, D, Hassell, A, Dickerson, SH, Ellis, B, Pennisi, C et al. (2004). "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 Research 64 (18): 6652–9. doi:10.1158/0008-5472.CAN-04-1168. PMID 15374980.
- ^ 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".
- ^ Nelson MH, Dolder CR (February 2006). "Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors". Ann Pharmacother 40 (2): 261–9. doi:10.1345/aph.1G387. PMID 16418322.
- ^ Geyer CE, Forster J, Lindquist D, et al. (December 2006). "Lapatinib plus capecitabine for HER2-positive advanced breast cancer". N. Engl. J. Med. 355 (26): 2733–43. doi:10.1056/NEJMoa064320. PMID 17192538.
- ^ Burris HA, Hurwitz HI, Dees EC, et al. (August 2005). "Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas". J. Clin. Oncol. 23 (23): 5305–13. doi:10.1200/JCO.2005.16.584. PMID 15955900.
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