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Revision as of 11:24, 23 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456968852 of page Lapatinib for the Chem/Drugbox validation project (updated: 'KEGG', 'CAS_number').  Latest revision as of 01:24, 12 October 2024 edit Whywhenwhohow (talk | contribs)Autopatrolled, Extended confirmed users, Pending changes reviewers49,153 edits infobox, links, templates; EU 
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{{Short description|Cancer medication}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Distinguish|apatinib}}
{{Drugbox
{{Use dmy dates|date=October 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 414583944
| verifiedrevid = 462089041
| IUPAC_name = ''N''-phenyl]-6-<br>-2-furyl]<br>quinazolin-4-amine
| image = Lapatinib.svg | image = Lapatinib.svg
| width = 250 | width = 275
| alt =
| image2 = Lapatinib 1XKK.png


<!--Clinical data--> <!-- Clinical data -->
| tradename = | pronounce =
| tradename = Tykerb, Tyverb, others
| Drugs.com = {{drugs.com|monograph|lapatinib-ditosylate}} | Drugs.com = {{drugs.com|monograph|lapatinib-ditosylate}}
| MedlinePlus = a607055 | MedlinePlus = a607055
| licence_EU = Tyverb | DailyMedID = Lapatinib
| pregnancy_AU = C
| licence_US = Lapatinib
| pregnancy_AU_comment =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_category =
| pregnancy_US = <!-- A / B / C / D / X -->
| routes_of_administration = ]
| pregnancy_category = D
| class =
| ATC_prefix = L01
| ATC_suffix = EH01
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = S4 | legal_AU = S4
| legal_AU_comment =
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C5, D1, D2, E, F1, F2, F3, F4 -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only | legal_US = Rx-only
| legal_status = | legal_US_comment =
| legal_EU = Rx-only
| routes_of_administration = Oral
| legal_EU_comment = <ref>{{cite web | title=Tyverb EPAR | website=European Medicines Agency (EMA) | date=10 June 2008 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/tyverb | access-date=12 October 2024}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = Rx-only


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = Variable, increased with food | bioavailability = Variable, increased with food
| protein_bound = >99% | protein_bound = >99%
| metabolism = ], mostly ]-mediated (minor ] and ] involvement) | metabolism = ], mostly ]-mediated (minor ] and ] involvement)
| metabolites =
| elimination_half-life = 24 hours
| onset =
| excretion = Mostly fecal
| elimination_half-life = 24 hours (repeated dosing), 14.2 hours (single dose)
| duration_of_action =
| excretion = Mostly ]


<!--Identifiers--> <!-- Identifiers -->
| index2_label = as salt
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = <!-- blanked - oldvalue: 231277-92-2 -->
| CAS_number = 231277-92-2
| CAS_supplemental = <br />{{CAS|388082-78-8}} (ditosylate)
| CAS_number2_Ref = {{cascite|changed|??}}
| ATC_prefix = L01
| CAS_number2 = 388082-78-8
| ATC_suffix = XE07
| CAS_supplemental =
| PubChem = 208908 | PubChem = 208908
| IUPHAR_ligand = 5692
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01259 | DrugBank = DB01259
| DrugBank2_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank2 = DBSALT001785
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 181006 | ChemSpiderID = 181006
| ChemSpiderID2_Ref = {{chemspidercite|correct|chemspider}}
| UNII_Ref = {{fdacite|changed|FDA}}
| ChemSpiderID2 = 9731817
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 0VUA21238F | UNII = 0VUA21238F
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = G873GX646R
| KEGG_Ref = {{keggcite|changed|kegg}} | KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = <!-- blanked - oldvalue: D04024 --> | KEGG = D08108
| ChEBI_Ref = {{ebicite|changed|EBI}} | KEGG2_Ref = {{keggcite|changed|kegg}}
| KEGG2 = D04024
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 49603 | ChEBI = 49603
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 554 | ChEMBL = 554
| ChEMBL2_Ref = {{ebicite|correct|EBI}}
| ChEMBL2 = 1201179
| NIAID_ChemDB =
| PDB_ligand = FMM
| synonyms =


<!--Chemical data--> <!-- Chemical and physical data -->
| IUPAC_name = ''N''-phenyl]-6-<br/>-2-furyl]<br/>quinazolin-4-amine
| C=29 | H=26 | Cl=1 | F=1 | N=4 | O=4 | S=1 | C=29 | H=26 | Cl=1 | F=1 | N=4 | O=4 | S=1
| molecular_weight = 581.058 g/mol
| smiles = CS(=O)(=O)CCNCc1ccc(o1)c2ccc3c(c2)c(ncn3)Nc4ccc(c(c4)Cl)OCc5cccc(c5)F | smiles = CS(=O)(=O)CCNCc1ccc(o1)c2ccc3c(c2)c(ncn3)Nc4ccc(c(c4)Cl)OCc5cccc(c5)F
| InChI = 1/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35)
| InChIKey = BCFGMOOMADDAQU-UHFFFAOYAL
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35) | StdInChI = 1S/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = BCFGMOOMADDAQU-UHFFFAOYSA-N | StdInChIKey = BCFGMOOMADDAQU-UHFFFAOYSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}

'''Lapatinib''' (]), used in the form of '''lapatinib ]''' (]) (trade names '''Tykerb''' and '''Tyverb''' marketed by ]) is an orally active ] for ] and other ]s.<ref name="pmid15163842">{{cite journal | vauthors = Burris HA | title = Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib | journal = The Oncologist | volume = 9 | pages = 10–15 | year = 2004 | issue = Suppl 3 | pmid = 15163842 | doi = 10.1634/theoncologist.9-suppl_3-10 | s2cid = 38907784 }}</ref> It is a dual ] which interrupts the ] and ] (EGFR) pathways.<ref name="futuredrugs"/> It is used in ] for HER2-positive breast cancer. It is used for the treatment of patients with advanced or ] whose tumors overexpress HER2 (ErbB2).<ref name="FDA">{{cite journal | vauthors = | title = Breast cancer drug approved for new indication | journal = Women's Health | volume = 6 | issue = 2 | pages = 173 | date = March 2010 | pmid = 20187722 | doi = 10.2217/whe.10.11 | publisher = Cancer.gov | doi-access = free }}</ref>

==Status==
In March 2007, the ] (FDA) approved lapatinib in ] for breast cancer patients already using ] (Xeloda).<ref name= futuredrugs /><ref name = "FDA"/> In January 2010, Tykerb received ] 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 (in combination with ]).<ref name="FDA" />

Pharmaceutical company ] (GSK) markets the drug under the proprietary names Tykerb (mostly U.S.) and Tyverb (mostly Europe and Russia).<ref name="GSK marketing">{{cite press release | title = GlaxoSmithKline receives marketing authorisation in the EU for Tyverb (lapatinib), the first oral targeted therapy for ErbB2-positive breast cancer | publisher = ] | date = 2008-06-12 | url = http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10063.htm | access-date = 2008-06-21 | url-status = dead | archive-url = https://web.archive.org/web/20080615022955/http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10063.htm | archive-date = 2008-06-15 }}</ref> The drug currently has approval for sale and clinical use in the US,<ref name= futuredrugs /><ref name="GSK marketing"/> Australia,<ref name= futuredrugs /> Bahrain,<ref name= futuredrugs /> Kuwait,<ref name= futuredrugs /> Venezuela,<ref name= futuredrugs /> Brazil,<ref name=PR>{{cite press release |url=http://www.medicalnewstoday.com/articles/72987.php |title=GlaxoSmithKline Reports Positive New Data On Tykerb (lapatinib) At The 2007 American Society Of Clinical Oncology (ASCO) Annual Meeting |date=June 4, 2007 |publisher=Medical News Today |access-date=December 2, 2008 |archive-date=April 13, 2010 |archive-url=https://web.archive.org/web/20100413212316/http://www.medicalnewstoday.com/articles/72987.php |url-status=dead }} Retrieved December 2, 2008.</ref> New Zealand,<ref name=PR/> South Korea,<ref name=PR/> Switzerland,<ref name="GSK marketing"/> Japan, Jordan, the European Union, Lebanon, India and Pakistan.<ref name="GSK marketing"/>

In August 2013, India's Intellectual Property Appellate Board revoked the patent for Glaxo's Tykerb citing its derivative status, while upholding at the same time the original patent granted for lapatinib.<ref>{{cite news | vauthors = Kulkarni K | title = India revokes GSK cancer drug patent in latest Big Pharma blow | newspaper = Reuters | location = Mumbai, India | date = 2 August 2013 | url = https://www.reuters.com/article/india-gsk-idUSL4N0G318920130802 | access-date = 2 August 2013}}</ref>

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.<ref name="pmid19422222">{{cite journal | vauthors = Cragg GM, Grothaus PG, Newman DJ | title = Impact of natural products on developing new anti-cancer agents | journal = Chemical Reviews | volume = 109 | issue = 7 | pages = 3012–43 | date = July 2009 | pmid = 19422222 | doi = 10.1021/cr900019j }}</ref>

==Mode of action==

===Biochemistry===
Lapatinib ] the ] activity associated with two ]s, ] (epidermal growth factor receptor) and ] (human EGFR type 2).<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = 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 | journal = Cancer Research | volume = 64 | issue = 18 | pages = 6652–6659 | date = September 2004 | pmid = 15374980 | doi = 10.1158/0008-5472.CAN-04-1168 | name-list-style = vanc | doi-access = free }}</ref> Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women.<ref name="futuredrugs">{{cite journal | vauthors = Higa GM, Abraham J | title = Lapatinib in the treatment of breast cancer | journal = Expert Review of Anticancer Therapy | volume = 7 | issue = 9 | pages = 1183–1192 | date = September 2007 | pmid = 17892419 | doi = 10.1586/14737140.7.9.1183 | s2cid = 36837880 }}</ref>

Like ], lapatinib is a ] shown to decrease tumor-causing breast ].<ref name="European Breast Cancer Conference 6">{{cite conference | vauthors = Rodriguez A |date=April 2008 |title=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 |url=http://www.ecco-org.eu/News/Press-room/Press-release/page.aspx/439?xf_itemId=265&xf_catId=27 |url-status=dead |archive-url=https://web.archive.org/web/20081126082044/http://www.ecco-org.eu/News/Press-room/Press-release/page.aspx/439?xf_itemId=265&xf_catId=27 |archive-date=2008-11-26 }}</ref>

Lapatinib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFR/HER2 protein ] ], preventing self-] and subsequent activation of the signal mechanism (see ]).<ref name="pmid16418322">{{cite journal | vauthors = Nelson MH, Dolder CR | title = Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors | journal = The Annals of Pharmacotherapy | volume = 40 | issue = 2 | pages = 261–269 | date = February 2006 | pmid = 16418322 | doi = 10.1345/aph.1G387 | s2cid = 21622641 }}</ref>

===Clinical application===

====Breast cancer====
Lapatinib is used as a treatment for women's breast cancer in treatment-naïve, ER+/EGFR+/HER2+ breast cancer patients and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as ], ]-derived drugs, or ] (Herceptin).

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 ] 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.<ref name="NEJM +">{{cite journal | vauthors = Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D | display-authors = 6 | title = Lapatinib plus capecitabine for HER2-positive advanced breast cancer | journal = The New England Journal of Medicine | volume = 355 | issue = 26 | pages = 2733–2743 | date = December 2006 | pmid = 17192538 | doi = 10.1056/NEJMoa064320 | doi-access = free }}</ref> The outcome of this study resulted in a somewhat complex and rather specific initial ] for lapatinib—use only in ] with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab.

Early clinical trials have been performed suggesting that high dose intermittent lapatinib might have better efficacy with manageable toxicities in the treatment of ]-overexpressing breast cancers.<ref>{{cite journal | vauthors = Chien AJ, Munster PN, Melisko ME, Rugo HS, Park JW, Goga A, Auerback G, Khanafshar E, Ordovas K, Koch KM, Moasser MM | display-authors = 6 | title = Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer | journal = Journal of Clinical Oncology | volume = 32 | issue = 14 | pages = 1472–1479 | date = May 2014 | pmid = 24711549 | pmc = 4017711 | doi = 10.1200/JCO.2013.52.1161 }}</ref>

==Adverse effects==
Like many small molecule tyrosine kinase inhibitors, lapatinib is regarded as well tolerated. The most common ] reported are ], ], ] and ]es.<ref name=futuredrugs /><ref name="pmid15955900">{{cite journal | vauthors = Burris HA, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O'Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL | display-authors = 6 | title = 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 | journal = Journal of Clinical Oncology | volume = 23 | issue = 23 | pages = 5305–5313 | date = August 2005 | pmid = 15955900 | doi = 10.1200/JCO.2005.16.584 | doi-access = free }}</ref> Of note, lapatinib related rash is associated with improved outcome.<ref name="pmid27098150">{{cite journal | vauthors = Sonnenblick A, de Azambuja E, Agbor-Tarh D, Bradbury I, Campbell C, Huang Y, Dueck AC, Pritchard KI, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Perez EA, Piccart M, Azim HA | display-authors = 6 | title = Lapatinib-Related Rash and Breast Cancer Outcome in the ALTTO Phase III Randomized Trial | journal = Journal of the National Cancer Institute | volume = 108 | issue = 8 | date = August 2016 | pages = djw037 | pmid = 27098150 | pmc = 5017935 | doi = 10.1093/jnci/djw037 }}</ref> In clinical studies elevated liver enzymes have been reported. ] has been observed with the use of lapatinib ditosylate but there are no reports of ]. Caution is advised in patients with hypokalaemia, hypomagnesaemia, congenital long QT syndrome, or with coadministration of medicines known to cause QT prolongation. In combination with ], reversible decreased left ] function are common (2%).<ref>{{cite web | work = NCI Cancer Drug Information | url = http://www.cancer.gov/cancertopics/druginfo/fda-lapatinib | title = FDA Approval for Lapatinib Ditosylate (Tykerb®) | archive-url = https://web.archive.org/web/20150406011929/http://www.cancer.gov/cancertopics/druginfo/fda-lapatinib | archive-date=2015-04-06 }}</ref>

==Ongoing trials in gastric cancer==
Phase III study designed to assess lapatinib in combination with chemotherapy for advanced HER2-positive gastric cancer in 2013 failed to meet the primary endpoint of improved overall survival (OS) against chemotherapy alone. The trial did not discover new safety signals, while the median OS for patients in the lapatinib and chemotherapy group was 12.2 months against 10.5 months for patients in the placebo plus chemotherapy. Secondary endpoints of the randomized, double-blinded study, were progression-free survival (PFS), response rate and duration of response. Median PFS was 6 months, response rate was 53% and the duration of response was 7.3 months in the investigational combination chemotherapy group compared to median PFS of 5.4 months, response rate of 39% and duration of response of 5.6 months for patients in chemotherapy alone group. Diarrhoea, vomiting, anemia, dehydration and nausea were serious adverse events (SAE) reported in over 2% of patients in the investigational combination chemotherapy group, while vomiting was the most common SAE noted in the chemotherapy group.<ref name="GSK">{{cite web | url = http://www.bioportfolio.com/news/article/1492867/GSK-Tykerb-Tyverb-Phase-III-gastric-cancer-study-fails-to-meet-primary.html | title = Tykerb/Tyverb Phase III gastric cancer study fails to meet primary endpoint | archive-url = https://web.archive.org/web/20150110162423/http://www.bioportfolio.com/news/article/1492867/GSK-Tykerb-Tyverb-Phase-III-gastric-cancer-study-fails-to-meet-primary.html | archive-date= 10 January 2015 }}</ref>

== References ==
{{Reflist}}

== External links ==
* {{cite web | title=Lapatinib Ditosylate | work=NCI Drug Dictionary | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/lapatinib-ditosylate }}
* {{cite web | title=Lapatinib Ditosylate | website=National Cancer Institute | date=16 March 2007 | url=https://www.cancer.gov/about-cancer/treatment/drugs/lapatinibditosylate }}

{{Extracellular chemotherapeutic agents}}
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