Pharmaceutical Approval Update: Lapatinib (Tykerb)
Manufacturer: GlaxoSmithKline, Research Triangle Park, NC
Indication: Lapatinib is indicated in combination with capecitabine (Xeloda, Roche) for patients with advanced or metastatic breast cancer whose tumors overexpress a marker called human epidermal receptor type-2 (HER-2) and who have received prior therapy, including an anthracycline, a tax-ane, and trastuzumab (Herceptin, Genentech).
Drug Class: Lapatinib is a small-molecule agent and a member of the 4-anilinoquinazoline class of kinase inhibitors. It is present as the monohydrate of the ditosylate salt. Its chemical name is A-(3-chloro-4-{[(3-fluorophenyl) methyl] oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4-methylbenzenesulfonate) monohydrate. The molecular formula is C29H26C1FN4O4 S(C7H8O3S)2H2O. canadian discount pharmacy
Uniqueness of Product: Lapatinib inhibits the intra-cellular tyrosine kinase domains of both epidermal growth factor receptor (EGFR [ErbB-1]) and human epidermal receptor type 2 (HER-2 [ErbB-2]) receptors, with estimated apparent kinase (Kiapp) values of 3 nM and 13 nM, respectively. Its dissociation half-life is 300 minutes or greater. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.
An additive effect was demonstrated in an in vitro study. Lapatinib and 5-fluorouracil (5-FU), the active metabolite of capecitabine, were used in combination in the four 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 media in vitro. These findings suggest no cross-resistance between these two agents.
Warnings and Precautions:
Decreased left ventricular ejection fraction. Lapatinib may decrease left ventricular ejection fraction (LVEF). In the randomized clinical trial, most of the decreases in LVEF (more than 60%) occurred within the first nine weeks of treatment; however, data on long-term exposure are limited.
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Caution should be exercised in patients with conditions that might impair LV function. LVEF should be evaluated in all patients before lapatinib treatment is begun to ensure that the baseline LVEF is within the institution’s normal limits. The LVEF should continue to be evaluated during treatment to ensure that it does not fall below normal limits.
Severe hepatic impairment. For patients with severe hepatic impairment, a dose reduction should be considered.
Diarrhea. Diarrhea, sometimes severe, has been reported during treatment with lapatinib. Proactive management with antidiarrheal agents is important. In severe cases, oral or IV electrolytes and fluids may be needed and therapy may have to be interrupted or discontinued.
QT prolongation. QT prolongation, as measured by the automated machine-read evaluation of electrocardiograms (ECGs), was observed in an uncontrolled, open-label, dose-escalation study of lapatinib in patients with advanced cancer. Lapatinib should be administered with caution in patients who have or who may develop a prolonged corrected QT (QTc) interval, including patients with hypokalemia or hypo-magnesemia, those with congenital long-QT syndrome, patients taking antiarrhythmic agents or other products leading to QT prolongation, and patients receiving cumulative high-dose anthracycline therapy. Hypokalemia or hypomag-nesemia should be corrected before lapatinib administration. Prescribers should consider baseline and on-treatment ECGs with QT measurements.
Pregnancy. As a Pregnancy Category D agent, lapatinib can cause fetal harm when given during pregnancy. In one study, pregnant rats were given lapatinib 120 mg/kg per day during organogenesis and through lactation. This dose is approximately 6.4 times the human clinical exposure, based on area-under-the-curve (AUC) concentration. By the fourth day after birth, 91% of the pups had died; of the pups that were given 60 mg/kg per day, 34% were dead. The highest dose that had no effect was 20 mg/kg per day (approximately equal to the human clinical exposure based on AUC concentration). erectalis tablets
Lapatinib was studied for its effects on embryofetal development in pregnant rats and rabbits that were given oral doses of 30, 60, and 120 mg/kg per day. There were no teratogenic effects, but minor anomalies (i.e., left-sided umbilical artery, cervical rib, and precocious ossification) occurred in the rats at the maternally toxic dose of 120 mg/kg per day.
In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg per day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC concentration). The drug was also associated with abortions at doses of 120 mg/kg per day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.
No adequate or well-controlled studies with lapatinib have been conducted in pregnant women. Women should be advised not to become pregnant when taking lapatinib. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazards to the fetus.
Dosage and Administration: The recommended dose of lapatinib is 1,250 mg (five tablets) orally once daily on days one to 21 continuously in combination with capecitabine 2,000 mg/m2 per day (orally in two doses approximately 12 hours apart) on days one to 14 in a repeating 21-day cycle. Lapatinib should be taken at least one hour before or one hour after a meal. Dividing the once-daily dose is not recommended.
Capecitabine should be taken with food or within 30 minutes after food is eaten. If a day’s dose is missed, the dose should not be doubled the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.
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Commentary: The presence of the HER-2 marker in cancerous tissue signals a cancer that is usually more aggressive than the typical breast cancer. The marker is present in approximately 20% of the estimated 178,480 invasive breast cancers that are expected to be diagnosed in women in the U.S. in 2007. This form of breast cancer usually occurs in younger patients. Trastuzumab, which targets this abnormality in breast cancer tissue, has improved response rates and lengthened survival time for many women. It has not always been a cure, but it is a major step forward.
In patients who are unresponsive to trastuzumab, lapatinib in combination with capecitabine is now available for patients with advanced or metastatic breast cancer whose tumors over-express HER-2 and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. It is the first targeted once-daily oral treatment option for these patients and represents a significant breakthrough for women with advanced HER-2 (ErbB-2)-positive breast cancer. Lapatinib inhibits two validated targets in oncology, the kinase components of the EGFR (ErbB-1) and HER-2 (ErbB-2) receptors,
commonly associated with cancer cell proliferation and tumor growth.
This agent, when combined with capecitabine, can be effective for disease that has progressed despite previous
therapies. The approval of Tykerb reflects more than 60 clinical trials and investigator-initiated collaborative research studies.