Lapatinib, a new member of the 4-anilinoquinazoline class of RTK inhibitors
(RTKIs), was launched as an oral treatment for breast cancer.
Lapatinib has dual affinity for EGFR and HER2 tyrosine kinases. It is indicated
in combination with capecitabine for treating patients with advanced or
metastatic breast cancer whose tumors overexpress HER2 and who have
received prior therapy including an anthracycline, a taxane, and trastuzumab.
Previously marketed drugs from the 4-anilinoquinazoline class include
erlotinib (Tarceva) and gefitinib (IressaTM), both of which are indicated for
treating non-small-cell lung cancer (NSCLC). As with erlotinib and gefitinib, To Market, To Market 2007 475 lapatinib is an ATP-competitive kinase inhibitor. It inhibits the tyrosine kinase activity EGFR and HER-2 with apparent Ki values of 3 and 13 nM, respectively, and has slow off-rate kinetics (t1/2X300 min).
In addition, dividing the daily dose of lapatinib results in approximately 2-fold higher exposure at steady state compared to the same total dose administered once daily.
The chemical synthesis of lapatinib entails the condensation of 4-chloro-6-iodoquinazoline and 3-chloro-4-(3-fluorobenzyloxy)aniline to produce a diaryl amine intermediate followed by Stille coupling of the iodo group with 5-dioxolanyl-2-(tributylstannyl)furan and subsequent acid hydrolysis of the cyclic ketal to the corresponding aldehyde. Finally, reductive amination of the aldehyde intermediate with 2-(methanesulfonyl) ethylamine in the presence of sodium triacetoxyborohydride produces lapatinib.
An antineoplastic agent used in breast cancer research
antineoplastic, tyrosine kinase inhibitor
Lapatinib Ditosylate (GW572016, GW2016, Tykerb, Tyverb) is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM, respectively.
Lapatinib, used in the form of Lapatinib Ditosylate, is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM, respectively.
ChEBI: Lapatinib is an organofluorine compound, an organochlorine compound, a member of quinazolines and a member of furans. It has a role as an antineoplastic agent and a tyrosine kinase inhibitor. It is functionally related to a monofluorobenzene.
Potentially hazardous interactions with other drugs
Antibacterials: avoid with rifabutin, rifampicin and
Antidepressants: avoid with St John’s wort.
Antidiabetics: avoid with repaglinide.
Antiepileptics: concentration reduced by
carbamazepine - avoid; possibly reduced
fosphenytoin and phenytoin concentration - avoid.
Antifungals: concentration increased by ketoconazole
- avoid; avoid with itraconazole, posaconazole and
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis); avoid with pimozide.
Antivirals: avoid with boceprevir, ritonavir and
Cytotoxics: concentration of pazopanib increased;
possible increased risk of neutropenia with docetaxel
and paclitaxel; concentration of active metabolite of
irinotecan increased, consider reducing irinotecan
Grapefruit juice: avoid concomitant us
Extensive hepatic metabolism, mainly by cytochrome
P450 isoenzymes CYP3A4 and CYP3A5; CYP2C19
and CYP2C8 account for some minor metabolism.
About 27% and 14% of an oral dose is recovered in the
faeces, as parent lapatinib and metabolites, respectively;
renal excretion is negligible.
1) Wood?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 Res.,?64?6652
2) Burris?et al. (2004),?Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib;? Oncologist,?9?10
3) Chu?et al. (2005),?The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016) cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer;? Cancer Res.,?65?18