Lapatinib Anticancer [4347

Country of origin: US Originator: GSK

First US

introduction: Introduced by: Trade name: CAS registry no: Molecular weight:

GSK Tykerb 231277-92-2 581.06

Lapatinib, a new member of the 4-anilinoquinazoline class of RTK inhibitors (RTKIs), was launched last year 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 (Iressa™), both of which are indicated for treating non-small-cell lung cancer (NSCLC). As with erlotinib and gefitinib, lapatinib is an ATP-competitive kinase inhibitor. It inhibits the tyrosine kinase activity EGFR and HER-2 with apparent Kj values of 3 and 13 nM, respectively, and has slow off-rate kinetics (ti/2X300min). Oral absorption of lapatinib is incomplete and variable. Peak plasma concentrations (Cmax) are achieved approximately 4 h after administration, and steady state is achieved within 6-7 days of daily dosing. Systemic exposure to lapatinib increases when administered with food. 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 terminal half-life following a single dose of lapatinib is 14.2 h, and accumulation with repeated dosing indicates an effective half-life of 24 h. Lapatinib has high protein binding (>99%). In vitro studies indicate that lapatinib is a substrate for the efflux transporters breast cancer resistance protein and Pgp. Elimination of lapatinib is primarily through metabolism, with approximately 27% of the oral dose excreted unchanged in feces and <2% in urine. The metabolism of lapatinib is mediated mainly by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8, to a variety of oxidation products. The recommended dose of lapatinib is 1,250 mg (five tablets) given orally once daily on days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (taken orally in 2 doses approximately 12 h apart) on days 1-14 in a repeating 21-day cycle. The clinical efficacy of lapatinib in combination with capecitabine was demonstrated in a Phase III trial in 399 patients with locally advanced or metastatic breast cancer refractory to anthracyclines, taxanes, and trastuzumab. Subjects were randomized to receive either lapatinib 1,250 mg/day plus capecitabine, or capecitabine alone. The primary endpoint was time to progression (TTP) defined as time from randomization to tumor progression or death related to breast cancer. The median TTP was 23.9 weeks for the combination treatment versus 18.3 weeks for capecitabine alone, with a response rate of 31.8% versus 17.4%, respectively. The most common adverse events associated with lapatinib treatment include diarrhea, hand-foot syndrome, nausea, rash, vomiting, and fatigue. Lapatinib has been reported to decrease left ventricular ejection fraction (LVEF), a measure of the strength of the heart's pumping capacity. LVEF should be assessed in all patients before and during treatment. QT prolongation also has been reported in patients treated with lapatinib. Caution should be exercised in administering this agent to patients who have or who may develop prolongation of QTc. In addition, dose adjustments may be necessary when administered concomitantly with drugs that are strong inhibitors or inducers of CYP3A4. 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.

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