Lapatinib

581.0575432

581.06

1806241-263-5

0VUA21238F

745750

DTXSID7046675

C26653

L01XE07|L - Antineoplastic and immunomodulating agents

2934999090

115

5.1

Solid

1.4±0.1 g/cm3

750.7°C at 760 mmHg

407.8±32.9 °C

1.645

2.23e-02 g/L

Store at 25 deg C (77 deg F); excursions permitted to 15 deg to 30 deg C (59 deg to 86 deg F).

1.63X10-17 mm Hg at 25 deg C (est)

Henry's Law constant = 4.93X10-22 atm-cu m/mol at 25 °C (est)

pKa1 = 3.80 (amine); pKa2 = 7.20 (amine)

Hydroxyl radical reaction rate constant = 3.04X10-10 cu cm/molec-sec at 25 °C (est)

II

6.1

UN 3275 6.1/PG 2

3

R10:Flammable. R23/24/25:Toxic by inhalation, in contact with skin and if swallowed . R34:Causes burns. R36/37/38:Irritating to eyes, respiratory system and skin .

S26-S36/37/39-S45-S24/25-S16

T,F

Stable if stored as directed; avoid strong oxidizing agents.

P201, P202, P260, P263, P264, P270, P273, P281, P308+P313, P314, P405, P501

H360

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including lapatinib ditosylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Lapatinib ditosylate/

|Danger|H360 (60%): May damage fertility or the unborn child [Danger Reproductive toxicity]|P201, P202, P260, P263, P264, P270, P273, P281, P308+P313, P314, P405, and P501|Aggregated GHS information provided by 5 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Personal protective equipment as follows: Breathing equipment: NIOSH/MSHA-approved respirator. Protection of hands: chemical-resistant rubber gloves. Eye protection: chemical safety goggles.

Suitable extinguishing agents: water spray, carbon dioxide, dry chemical powder or foam. Protective equipment: wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes.

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves Measures for cleaning/collecting absorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, fedreal, state and local regulations/.

Handling should only be performed by personnel trained and familiar with handling of potent active pharmaceutical ingredients.|Information for safe handling: avoid inhalation and contact with skin, eyes and clothing ... .

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.|IDENTIFICATION AND USE: Lapatinib is a yellow solid formulated into film-coated tablets. Lapatinib, an inhibitor of human epidermal growth factor receptor type 2 (HER2/ERBB2) and epidermal growth factor receptor (HER1/EGFR/ERBB1) tyrosine kinases, is an antineoplastic agent. It is used in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. It is also used in combination with letrozole 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. HUMAN EXPOSURE AND TOXICITY: Asymptomatic and symptomatic cases of overdose have been reported. The doses ranged from 2,500 to 9,000 mg daily, the duration varied between 1 and 17 days. Symptoms observed include lapatinib-associated events and in some cases sore scalp, sinus tachycardia (with otherwise normal ECG), and/or mucosal inflammation. At therapeutic doses, hepatotoxicity, manifested as increases in serum concentrations of aminotransferases and bilirubin, has been observed in clinical trials and post-marketing experience with lapatnib. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur within days to several months after initiation of treatment. Women should avoid the use of lapatinib during pregnancy. While there are not adequate and well-controlled studies in pregnant women, lapatinib has been associated with adverse reproductive effects in animals. If used during pregnancy, the patient should be apprised of the potential fetal hazard. ANIMAL STUDIES: While there was no evidence of carcinogenicity in a two year mouse study, increased mortality which was related to skin toxicities was observed in males at 150 and 300 mg/kg/day and in females at 300 mg/kg/day. In a two-year rat carcinogenicity study, increased mortality was observed in males at 500 mg/kg/day and females at 300 mg/kg/day, and was related to skin toxicities. Renal infarcts and papillary necrosis were observed in females from 60 mg/kg/day and 180 mg/kg/day, respectively. An increased incidence of benign hemangioma of the mesenteric lymph nodes was noted in males from 120 mg/kg/day and in females at 180 mg/kg/day but was within background range. The clinical significance of these findings to humans is not known. Lapatinib did not affect male or female rat gonadal function, mating, or fertility at doses up to 120 mg/kg/day in females and up to 180 mg/kg/day in males. Studies in pregnant rats and rabbits revealed no teratogenic effects. However, in rats, minor anomalies (left-sided umbilical artery, cervical rib and precocious ossification) occurred at the maternally toxic dose of 120 mg/kg/day. In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day and abortions at 120 mg/kg/day. At maternally toxic doses, decreased fetal body weights, decreased number of live fetuses and minor skeletal variations were noted. Lapatinib was not clastogenic or mutagenic in a battery of assays including the Chinese hamster chromosome aberration assay, the Ames assay, human lymphocyte chromosome aberration assay and an in vivo rat bone marrow chromosome aberration assay.

Elevations in serum aminotransferase levels are common during lapatinib therapy, occurring in up to half of patients. Values greater than 5 times the upper limit of normal (ULN) occur in 2% to 6% of patients but are usually transient and asymptomatic. Dose adjustments or temporary discontinuations are rarely required for liver test abnormalities.

Grapefruit products should be avoided because of the potential for increased plasma lapatinib concentrations.|In patients receiving lapatinib and paclitaxel (a CYP2C8 and P-gp substrate) concomitantly, systemic exposure (AUC over 24 hours) of paclitaxel was increased by 23%. However, the manufacturer states that because of limitations of the study design, these data may underestimate the potential increase in paclitaxel exposure during concomitant use.|Concomitant administration of lapatinib and oral digoxin (a P-gp substrate) increased systemic exposure (AUC) of digoxin by approximately 2.8-fold. In patients receiving digoxin, serum digoxin concentrations should be measured prior to initiation of lapatinib therapy and monitored throughout concomitant therapy. If serum digoxin concentrations exceed 1.2 ng/mL, digoxin dosage should be reduced by 50%.|Because lapatinib may cause prolongation of the QT interval, lapatinib should be used with caution in patients receiving concomitant therapy with other drugs (e.g., antiarrhythmic agents) known to prolong the QT interval.|For more Interactions (Complete) data for Lapatinib (10 total), please visit the HSDB record page.

Lapatinib may cause fetal harm; fetal anomalies, abortion, and death of offspring within days after birth have been demonstrated in animals. Pregnancy should be avoided during therapy. If lapatinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.|Lapatinib should be used with caution in patients with severe hepatic impairment (Child-Pugh class C); systemic exposure to the drug may be increased. Dosage reduction should be considered in patients with severe hepatic impairment.

Highly bound (>99%) to albumin and alpha-1 acid glycoprotein

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.|Tyverb is indicated for the treatment of patients with breast cancer, whose tumours overexpress HER2 (ErbB2):in combination with capecitabine for patients with advanced or metastatic disease with progression following prior therapy, which must have included anthracyclines and taxanes and therapy with trastuzumab in the metastatic setting;in combination with trastuzumab for patients with hormone-receptor-negative metastatic disease that has progressed on prior trastuzumab therapy or therapies in combination with chemotherapy;in combination with an aromatase inhibitor for post-menopausal women with hormone-receptor-positive metastatic disease, not currently intended for chemotherapy. The patients in the registration study had not previously been treated with trastuzumab or an aromatase inhibitor. No data are available on the efficacy of this combination relative to trastuzumab in combination with an aromatase inhibitor in this patient population.|Drug: Lapatinibditosylate

Lapatinib is a small molecule inhibitor of several tyrosine kinase receptors involved in tumor cell growth that is used in the therapy of advanced breast cancer and other solid tumors. Lapatinib therapy is associated with transient elevations in serum aminotransferase levels and rare instances of clinically apparent acute liver injury.

Antineoplastic Agents

Antineoplastic Agents; Protein Kinase Inhibitors|Tykerb is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Limitation of Use: Patients should have disease progression on trastuzumab prior to initiation of treatment with Tykerb in combination with capecitabine. /Included in US product label/|Tykerb is indicated in combination with letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated. /Included in US product label/|EXPL THER Although there are effective HER2-targeted agents, novel combination strategies in HER2-overexpressing breast cancers are needed for patients whose tumors develop drug resistance. To develop new therapeutic strategy, ... the combinational effect of entinostat, an oral isoform-selective histone deacetylase type I inhibitor, and lapatinib, a HER2/EGFR dual tyrosine kinase inhibitor, in HER2+ breast cancer cells /was investigated/. ... The combinational synergistic effect and its mechanism by CellTiter Blue assay, flow cytometry, anchorage-independent growth, quantitative real-time PCR, small interfering RNA, Western blotting, and mammary fat pad xenograft mouse models /was assessed/. /It was/ found that compared with entinostat or lapatinib alone, the two drugs in combination synergistically inhibited proliferation (P < 0.001), reduced in vitro colony formation (P < 0.05), and resulted in significant in vivo tumor shrinkage or growth inhibition in two xenograft mouse models (BT474 and SUM190, P < 0.001). The synergistic anti-tumor activity of the entinostat/lapatinib combination was due to downregulation of phosphorylated Akt, which activated transcriptional activity of FOXO3, resulting in induction of Bim1 (a BH3 domain-containing pro-apoptotic protein). Furthermore, entinostat sensitized trastuzumab/lapatinib-resistance-HER2-overexpressing cells to the trastuzumab/lapatinib combination and enhanced the anti-proliferation effect compare with single or double combination treatment. This study provides evidence that entinostat has enhanced anti-tumor effect in combination with HER2-targeted reagent, lapatinib, and resulting in induction of apoptosis by FOXO3-mediated Bim1 expression. ... Findings justifies for conducting a clinical trial of combinational treatment with entinostat, lapatinib, and trastuzumab in patients with HER2-overexpressing breast cancer resistant to trastuzumab-based treatment.

/BOXED WARNING/ WARNING: HEPATOTOXICITY. Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain.|Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with Tykerb should be discontinued and patients should not be retreated with Tykerb.|Lapatinib may cause fetal harm; fetal anomalies, abortion, and death of offspring within days after birth have been demonstrated in animals. Pregnancy should be avoided during therapy. If lapatinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.|FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./|For more Drug Warnings (Complete) data for Lapatinib (14 total), please visit the HSDB record page.

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.

Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)|Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

Absorption following oral administration of lapatinib is incomplete and variable.|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.|After administration of a single oral dose of (14)C-lapatinib, the predominant route of elimination of drug-related material in the mouse, rat and dog was in the feces, with very little urinary excretion. Most of the dose was eliminated within 48 hours post-dose.|Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (<2%) renal excretion. Recovery of parent lapatinib in feces accounts for a median of 27% (range 3% to 67%) of an oral dose.|Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values were approximately 3- and 4-fold higher (Cmax approximately 2.5- and 3-fold higher) when administered with a low-fat (5% fat-500 calories) or with a high-fat (50% fat-1,000 calories) meal, respectively.|Lapatinib is highly bound (>99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters breast cancer-resistance protein (BCRP, ABCG2) and P-glycoprotein (P-gp, ABCB1). Lapatinib has also been shown to inhibit P-gp, BCRP, and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.|For more Absorption, Distribution and Excretion (Complete) data for Lapatinib (7 total), please visit the HSDB record page.

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.|Lapatinib, an oral breast cancer drug, has recently been reported to be a mechanism-based inactivator of cytochrome P450 (P450) 3A4 and also an idiosyncratic hepatotoxicant. It was suggested that formation of a reactive quinoneimine metabolite was involved in mechanism-based inactivation (MBI) and/or hepatotoxicity. We investigated the mechanism of MBI of P450 3A4 by lapatinib. Liquid chromatography-mass spectrometry analysis of P450 3A4 after incubation with lapatinib did not show any peak corresponding to irreversible modifications. The enzymatic activity inactivated by lapatinib was completely restored by the addition of potassium ferricyanide. These results indicate that the mechanism of MBI by lapatinib is quasi-irreversible and mediated via metabolic intermediate complex (MI complex) formation. This finding was verified by the increase in a signature Soret absorbance at approximately 455 nm. Two amine oxidation products of the metabolism of lapatinib by P450 3A4 were characterized: N-hydroxy lapatinib (M3) and the oxime form of N-dealkylated lapatinib (M2), suggesting that a nitroso or another related intermediate generated from M3 is involved in MI complex formation. In contrast, P450 3A5 was much less susceptible to MBI by lapatinib via MI complex formation than P450 3A4. In addition, P450 3A5 had a significantly lower ability than 3A4 to generate M3, consistent with N-hydroxylation as the initial step in the pathway to MI complex formation. In conclusion, our results demonstrate that the primary mechanism for MBI of P450 3A4 by lapatinib is not irreversible modification by the quinoneimine metabolite, but quasi-irreversible MI complex formation mediated via oxidation of the secondary amine group of lapatinib.|Lapatinib undergoes extensive metabolism in humans to numerous oxidated and N- and O-dealkylated products. In vitro studies using human hepatocytes and microsomes indicated that lapatinib is primarily metabolised by CYP3A4 and CYP3A5, with smaller contributions from CYP2C8. Additional studies indicated that CYP1A2, 2D6, 2C9 and 2C19 may also be involved, but to a lesser extent. The most prominent metabolites are the carboxylic acid GW42393 and the O-dealkylated phenol GW690006. N-oxidation of the secondary aliphatic amine produced a cascade of about 8 minor metabolites. Relative to parent drug, GW690006 produced approximately equipotent inhibition of ErbB1-dependent tumour cell growth in vitro, but was approximately 100-fold less potent in ErbB2- dependent tumour cells. GW342393 was found to be approximately 40-fold less potent than parent drug in both ErbB1- and ErbB2-dependent tumour cells. They are unlikely to contribute to the biological activity of lapatinib.|Lapatinib, an oral tyrosine kinase inhibitor used for breast cancer, has been reported to cause idiosyncratic hepatotoxicity. Recently, it has been found that lapatinib forms a metabolite-inhibitor complex (MIC) with CYP3A4 via the formation of an alkylnitroso intermediate. Because CYP3A5 is highly polymorphic compared with CYP3A4 and also oxidizes lapatinib, we investigated the interactions of lapatinib with CYP3A5. Lapatinib inactivated CYP3A5 in a time-, concentration-, and NADPH-dependent manner using testosterone as a probe substrate with K(I) and k(inact) values of 0.0376 mM and 0.0226 min(-1), respectively. However, similar results were not obtained when midazolam was used as the probe substrate, suggesting that inactivation of CYP3A5 by lapatinib is site-specific. Poor recovery of CYP3A5 activity postdialysis and the lack of a Soret peak confirmed that lapatinib does not form a MIC with CYP3A5. The reduced CO difference spectrum further suggested that a large fraction of the reactive metabolite of lapatinib is covalently adducted to the apoprotein of CYP3A5. GSH trapping of a reactive metabolite of lapatinib formed by CYP3A5 confirmed the formation of a quinoneimine-GSH adduct derived from the O-dealkylated metabolite of lapatinib. In silico docking studies supported the preferential formation of an O-dealkylated metabolite of lapatinib by CYP3A5 compared with an N-hydroxylation reaction that is predominantly catalyzed by CYP3A4. In conclusion, lapatinib appears to be a mechanism-based inactivator of CYP3A5 via adduction of a quinoneimine metabolite.|Metabolism of lapatinib was assessed both quantitatively and qualitatively in the plasma and excreta of rats (10 mg/kg), dogs (10 mg/kg), mice (30 mg/kg) and humans (250 mg) following a single oral administration of (14)C-lapatinib. In general, (14)C-lapatinib was primarily metabolized, secreted in the bile and eliminated in the feces. In the nonclinical and clinical metabolism studies, urine samples were not analyzed due to the low percentage of the dose excreted by this route. In plasma, (14)C-lapatinib represented the largest single component in all species. Lapatinib was more extensively metabolised in male rats than in female rats, however the metabolic profiles were similar. In dogs and humans, 14C-lapatinib was the only quantifiable peak present. In humans, lapatinib accounted for only approximately half of the radioactivity in the plasma. The remaining radioactivity was attributed to at least 8 metabolites detected by LC-MS but below the limit of radiochemical quantification (approximately 5% of the total radioactivity in pooled plasma). These metabolites were attributed to the N-oxidation cascade that was also observed in vitro as well as in rats and mice. In both mice and rats, only a few of these metabolites were quantifiable in plasma by radiochemical detection, but all were characterized by mass spectrometry. Thus, no unique circulating metabolites were observed in humans

Single-dose terminal half life: 14.2 hours Effective multiple-dose half life: 24 hours|At clinical doses, the terminal phase half-life following a single dose was 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours.|In a mass-balance study, single 250 mg doses of (14)C-labelled lapatinib administered to 6 healthy volunteers produced serum concentrations of radio-labelled material representing parent drug and metabolites that peaked 4 hr after the dose and declined with a median half-life of 6 hr. Plasma concentrations of lapatinib declined with a half-life of 14 hours.

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.|Lapatinib (GW572016) is a small-molecule dual inhibitor of epidermal growth factor receptor (ErbB1) and ErbB2 receptor kinase activities currently in phase III clinical trials. ... Phosphoprotein and microarray analyses /were used/ to carry out targeted pathway studies of phosphorylation and gene expression changes in human breast cancer cell lines in the presence or absence of lapatinib. Studies were done in four breast cancer cell lines, two of which were responsive and two of which were nonresponsive to lapatinib. Responsive cell lines, BT474 and SKBr3, constitutively overexpress ErbB2 and show an IC(50) of 25 or 32 nmol/L for lapatinib, respectively. In contrast, nonresponsive MDA-MB-468 and T47D cells expressed a low basal level of ErbB2 and showed IC(50) values in the micromolar range. Cells responsive to lapatinib exhibited strong differential effects on multiple genes in the AKT pathway. After 12 hr of exposure to 1.0 umol/L of lapatinib, AKT1, MAPK9, HSPCA, IRAK1, and CCND1 transcripts were down-regulated 7- to 25-fold in responsive BT474 and SKBr3 cells. In contrast, lapatinib weakly down-regulated the AKT pathway in nonresponsive breast cancer cell lines (<5-fold down-regulation of most genes in the pathway). Furthermore, the proapoptotic gene FOXO3A, which is negatively regulated by AKT, was up-regulated 7- and 25-fold in lapatinib-responsive SKBr3 and BT474 cells, respectively. Phosphorylated Akt and Akt-mediated phosphorylation of FOXO3A also decreased in responsive breast cancer cell lines exposed to lapatinib. Gene expression profiling also revealed that lapatinib stimulated the expression of estrogen and progesterone receptors and modulated the expression of genes involved in cell cycle control, glycolysis, and fatty acid metabolism. In BT474 and T47D cells, which expressed moderate basal levels of the estrogen and progesterone receptors, 1.0 micromol/L of lapatinib induced expression by 7- to 11-fold. These data provide insight into the mechanism of action of lapatinib in breast cancer cells.|Lapatinib is a tyrosine kinase inhibitor which dually inhibits the growth factor receptors ErbB1 (epidermal growth factor receptor, EGFR) and ErbB2 (HER2). Lapatinib is a member of the 4-anilinoquinazoline class of kinase inhibitors. Members of this class of molecules have been shown to bind to the ATP binding site of protein kinases and compete with the ATP substrate. This blocks receptor phosphorylation and activation, preventing subsequent downstream signalling events. ErbB2 is one of four members of a family of genes encoding transmembrane receptors for growth factors, the other three being ErbB1 (EGFR or HER1), ErbB3 (HER3) and ErbB4 (HER4). There is evidence ... that induced overexpression of ErbB1 or ErbB2 receptors in cells in vitro produces phenotypes associated with oncogenic transformation, such as the ability to grow in soft agar and formation of tumors in nude mice. In vivo, overexpression of ErbB1 or ErbB2 has been reported in a variety of human tumors and has been associated with poor prognosis and reduced overall survival in patients with cancer. Several therapeutic strategies have been employed to block the ErbB2 signalling pathways as a means to improve the therapeutic efficacy of hormonal and chemotherapy regimens. The rationale for lapatinib use as an anticancer entity is that the blockade of the tyrosine kinase activity of ErbB1 or ErbB2 is expected to block the transforming activity that results from overexpression of these receptors.|Endometrial cancers have been recently molecularly characterized; amplifications of human epidermal growth factor receptor 2 (HER2) were seen in 25% of the serous-like tumors, and mutations in the PI(3)K/AKT pathways were seen in 93% of endometrioid tumors. These new findings about endometrial cancer suggest a potential for targeted therapy with lapatinib, a dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases. However, the clinical efficacy of lapatinib in phase II clinical trials for the treatment of endometrial cancers was only minimal. In this study, we investigated the signaling changes induced by lapatinib in endometrial cancer, which may improve its therapeutic efficacy in molecularly selected patient groups. ... One of the final molecular targets of lapatinib to be interstitial collagenase, matrix metallopeptidase 1 (MMP1) /was identified/. Lapatinib suppresses MMP1 through EGFR and HER2, and their downstream ERK and AKT signaling pathways. /It was/ also found that the activating protein-1 binding site of MMP1 promoter is required for its transcriptional activation, which may be unique for endometrial cancers. ... Results also showed that forced expression of active ERK or active AKT mutants rescued MMP1 expression from lapatinib suppression, further suggesting the importance of molecular selection to find appropriate patients with endometrial cancer for future clinical trials with any targeted therapies.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|There is no known antidote for overdoses of Tykerb. ... Because lapatinib is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib. Treatment of overdose with Tykerb should consist of general supportive measures.|For more Antidote and Emergency Treatment (Complete) data for Lapatinib (7 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with Tykerb should be discontinued and patients should not be retreated with Tykerb.|/SIGNS AND SYMPTOMS/ Asymptomatic and symptomatic cases of overdose have been reported. The doses ranged from 2,500 to 9,000 mg daily and where reported, the duration varied between 1 and 17 days. Symptoms observed include lapatinib-associated events and in some cases sore scalp, sinus tachycardia (with otherwise normal ECG), and/or mucosal inflammation.|/GENOTOXICITY/ Lapatinib was not clastogenic or mutagenic in a battery of assays including the ... human lymphocyte chromosome aberration assay ... .|/ALTERNATIVE and IN VITRO TESTS/ Lapatinib, an oral tyrosine kinase inhibitor used for breast cancer, has been reported to cause idiosyncratic hepatotoxicity. Recently, it has been found that lapatinib forms a metabolite-inhibitor complex (MIC) with CYP3A4 via the formation of an alkylnitroso intermediate. Because CYP3A5 is highly polymorphic compared with CYP3A4 and also oxidizes lapatinib, we investigated the interactions of lapatinib with CYP3A5. Lapatinib inactivated CYP3A5 in a time-, concentration-, and NADPH-dependent manner using testosterone as a probe substrate with K(I) and k(inact) values of 0.0376 mM and 0.0226 min(-1), respectively. However, similar results were not obtained when midazolam was used as the probe substrate, suggesting that inactivation of CYP3A5 by lapatinib is site-specific. Poor recovery of CYP3A5 activity postdialysis and the lack of a Soret peak confirmed that lapatinib does not form a MIC with CYP3A5. The reduced CO difference spectrum further suggested that a large fraction of the reactive metabolite of lapatinib is covalently adducted to the apoprotein of CYP3A5. GSH trapping of a reactive metabolite of lapatinib formed by CYP3A5 confirmed the formation of a quinoneimine-GSH adduct derived from the O-dealkylated metabolite of lapatinib. In silico docking studies supported the preferential formation of an O-dealkylated metabolite of lapatinib by CYP3A5 compared with an N-hydroxylation reaction that is predominantly catalyzed by CYP3A4. In conclusion, lapatinib appears to be a mechanism-based inactivator of CYP3A5 via adduction of a quinoneimine metabolite.|For more Human Toxicity Excerpts (Complete) data for Lapatinib (9 total), please visit the HSDB record page.

GW 282974X

Oral: Tablets, film-coated: 250 mg (of lapatinib), Tykerb (GlaxoSmithKline).

A simple, selective, rapid, precise and economical reverse-phase high-performance liquid chromatography method has been developed for the determination of lapatinib in tablet using gemcitabine hydrochloride as an internal standard. Chromatography was carried out on an ODS C-18 RP column (4.6 mm i.d. x250 mm) using a mixture of acetonitrile and water (50:50 v/v) as the mobile phase at a flow rate of 1.0 ml/min. The drug was monitored at 232 nm. The retention times for lapatinib and gemcitabine hydrochloride were found to be 4.25 plus or minus 0.05 and 6.10 plus or minus 0.05 min, respectively. The method produced linear responses in the concentration range of 2-60 ug/mL of lapatinib. The limit of detection and limit of quantitation were 0.265 and 0.884 ug/mL, respectively.

A selective and precise high-performance liquid chromatography ultraviolet method was developed and validated for the determination of lapatinib in human plasma. After protein precipitation with acetonitrile, lapatinib and sorafenib were separated using isocratic elution (on a C18 Ultrabase column using a mobile phase of acetonitrile/20 mM ammonium acetate in a proportion 53:47 (v/v) pumped at a constant flow rate of 1.2 mL/min). Quantification was performed at 260 nm. Calibration curves were linear over the range 0.2-10 ug/mL. Inter- and intraday coefficients of variation were less than 7%. The limit of detection and the lower limit of quantification were 0.1 and 0.2 ug/mL, respectively.|A highly sensitive and selective liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed to quantify cellular levels of the tyrosine kinase inhibitors (TKIs) dasatinib (Sprycel) and lapatinib (Tykerb, Tyverb). Cellular samples were extracted with a tert-butyl methyl ether:acetonitrile (3:1, v/v):1 M ammonium formate pH 3.5 (8:1, v/v) mixture. Separation was achieved on a Hyperclone BDS C18 (150 mm x 2.0 mm 3 microm) column with isocratic elution using a mobile phase of acetonitirile-10 mM ammonium formate, pH 4 (54:46, v/v), at a flow rate of 0.2 mL/min. The TKIs were quantified using a triple quadrupole mass spectrometer which was operated in multi-reaction-monitoring mode employing positive electrospray ionisation. The limit of detection and limit of quantification for lapatinib was determined to be 15 and 31 pg on column, respectively. The limit of detection and quantification for dasatinib was 3 and 15 pg on column, respectively.|A sensitive method for the determination of lapatinib (GW572016) in human plasma was developed using high-performance liquid chromatographic separation with tandem mass spectrometric detection. Plasma samples (100 microL) were prepared using solid phase extraction (SPE) columns, and 6.0 microL of the reconstituted eluate was injected onto a Phenomenex CuroSil-PFP 3 mu analytical column (50 mm x 2.0mm) with an isocratic mobile phase. Analytes were detected with a PE SCIEX API-365 LC-MS/MS system at unit (Q1) and low (Q3) resolution in positive multiple reaction monitoring mode (m/z 581 (precursor ion) to m/z 364 (product ion) for lapatinib). The mean recovery for lapatinib was 75% with a lower limit of quantification of 15 ng/mL (S/N=11.3, CV< or =14%). This method was validated over a linear range of 100-10,000 ng/mL, and results from a 5-day validation study demonstrated good within-day and between-day precision and accuracy. This method has been used to measure plasma lapatinib concentrations in a Phase I study in children with cancer.|LC-MS/MS determination in plasma.

Human drugs -> Tyverb -> EMA Drug Category|Protein kinase inhibitors -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients