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QuickView for lapatinib (compound)

Summary
General Info

PubChem

PubChem Compound 11557040

Name:	lapatinib
PubChem Compound ID:	11557040
Molecular formula:	C₄₃H₄₄ClFN₄O₁₁S₃
Molecular weight:	943.479 g/mol
Synonyms:	Lapatinib ditosylate (USAN); 388082-78-8; Lapatinib ditosylate; D04024

DrugBank

Identification

Name:	lapatinib
Name (isomeric):	DB01259
Drug Type:	small molecule
Synonyms:	GW 572016; GW572016; Lapatinib tosilate hydrate; FMM; Lapatinib ditosylate
Brand:	Tykerb, Tycerb
Category:	Antineoplastic Agents, Protein Kinase Inhibitors
CAS number:	388082-78-8

Pharmacology

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.
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 conjunct... show more » 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. show less «
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 m... show more » 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. show less «
Absorption:	Absorption following oral administration of lapatinib is incomplete and variable.
Protein binding:	Highly bound (>99%) to albumin and alpha-1 acid glycoprotein
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.
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.
Half Life:	Single-dose terminal half life: 14.2 hours Effective multiple-dose half life: 24 hours
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.
Affected organisms:	Humans and other mammals

Interactions

Drug interaction:

Thiothixene	May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Vorinostat	Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Tamsulosin	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.
Telithromycin	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.
Trazodone	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.

Thiothixene	May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Vorinostat	Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Tamsulosin	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.
Telithromycin	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.
Trazodone	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.
Tretinoin	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.
Tolterodine	Lapatinib may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.
Ziprasidone	Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
Artemether	Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Tacrolimus	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Lumefantrine	Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Voriconazole	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.
Toremifene	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.
Zuclopenthixol	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).
Topotecan	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.
Trimipramine	Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Tramadol	Lapatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

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Targets

Epidermal growth factor receptor

Isoform 2/truncated isoform may act as an antagonist

UniProt ID:

P00533

Gene:

EGFR

Actions:

antagonist

References:

Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL: Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002 Sep 12;21(41):6255-63.
View Article

Grana TM, Sartor CI, Cox AD: Epidermal growth factor receptor autocrine signaling in RIE-1 cells transformed by the Ras oncogene enhances radiation resistance. Cancer Res. 2003 Nov 15;63(22):7807-14.
View Article

Xia W, Liu LH, Ho P, Spector NL: Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene. 2004 Jan 22;23(3):646-53.
View Article

Zhou H, Kim YS, Peletier A, McCall W, Earp HS, Sartor CI: Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):344-52.
View Article

Langer CJ: Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):991-1002.
View Article

Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 2004;9 Suppl 3:10-5.
View Article

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.
View Article

Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Barco SD, Martin-Castillo B, Menendez JA: Lapatinib, a dual HER1/HER2 tyrosine kinase inhibitor, augments basal cleavage of HER2 extracellular domain (ECD) to inhibit HER2-driven cancer cell growth. J Cell Physiol. 2010 Jul 23.
View Article

Johnston SR, Leary A: Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc). 2006 Jul;42(7):441-53.
View Article

Tevaarwerk AJ, Kolesar JM: Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther. 2009;31 Pt 2:2332-48.
View Article

Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47.
View Article

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
View Article

Receptor tyrosine-protein kinase erbB-2

Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Not activated by EGF, TGF- alpha and amphiregulin

UniProt ID:

P04626

Gene:

ERBB2

Actions:

antagonist

References:

Langer CJ: Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):991-1002.
View Article

Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 2004;9 Suppl 3:10-5.
View Article

Johnston SR, Leary A: Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc). 2006 Jul;42(7):441-53.
View Article

Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47.
View Article

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
View Article

Enzymes

Transporters

Multidrug resistance protein 1

Antigen peptide transporter 1