AIMS AND BACKGROUND: Lapatinib is a tyrosine kinase inhibitor targeting epidermal growth factor receptors 1 (EGFR/HER1) and 2 (HER2) used in the treatment of patients with HER2-positive breast cancer. The aim of the present study was to determine lapatinib plasma levels in breast cancer patients treated with lapatinib plus capecitabine. PATIENTS AND METHODS: We assessed lapatinib plasma levels in blood samples from 21 breast cancer patients treated with lapatinib plus capecitabine using the standard regimen in an expanded access program. Liquid chromatography tandem mass spectrometry was used for measuring lapatinib plasma concentrations. The validated method was applied for measurement of 55 plasma samples. RESULTS: The median lapatinib plasma level was 5.09 μg/mL, with large interindividual differences. Patients of lower weight tended to have higher lapatinib plasma levels (Spearman correlation coefficient R = -0.435, P = 0.055). One patient's lapatinib plasma levels were markedly higher than those of the others, with a median level of 11.25 μg/mL and repeatedly exceeding 7.80 μg/mL. The treatment was terminated after 8 months when hyperbilirubinemia occurred. CONCLUSIONS: The lapatinib plasma levels reported here are twice as high as the clinically effective steady-state geometric mean maximum concentration. We conclude that increased lapatinib body levels occur when patients are in a nonfasting state at the time of drug intake and when lapatinib doses are not adjusted to low body weight or weight loss during treatment. In Europe, dose adjustments are not recommended in the case of hepatic function impairment. Thus, attention should be paid to changes in liver function test results in clinical practice, especially in patients of small stature and weight, given the risk of high plasma concentrations. Prospective lapatinib plasma level assessment in treated patients might be useful to confirm or refute the possible correlation of high lapatinib plasma levels with hepatic and/or other toxicities.
- MeSH
- chinazoliny aplikace a dávkování krev MeSH
- chromatografie kapalinová MeSH
- deoxycytidin aplikace a dávkování analogy a deriváty MeSH
- dospělí MeSH
- fluorouracil aplikace a dávkování analogy a deriváty MeSH
- hyperbilirubinemie chemicky indukované MeSH
- inhibitory proteinkinas aplikace a dávkování krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery krev MeSH
- nádory prsu krev farmakoterapie patologie MeSH
- prediktivní hodnota testů MeSH
- prospektivní studie MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- retrospektivní studie MeSH
- senioři MeSH
- staging nádorů MeSH
- stupeň nádoru MeSH
- tandemová hmotnostní spektrometrie MeSH
- tyrosinkinasy antagonisté a inhibitory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Background. Breast cancer treatment trends are currently based on tailored therapies using tumor and patient biomarkers. Lapatinib is the first dual inhibitor of HER1 (EGFR, ErbB1) and HER2 (ErbB2, Neu) tyrosine kinases to be used in clinical practice. However, only HER2 is currently used for therapy indications and new predictors for the treatment with lapatinib are sought. Methods and results. This minireview focuses on lapatinib and its role in breast cancer treatment. Preclinical and clinical studies as well as pharmacological characteristics are briefly reviewed while the focus is on efficacy assessment including predictive factors for therapy outcome. Conclusion. Lapatinib (Tykerb/Tyverb) was Food and Drug Administration (FDA) approved in 2007 for use in combination with capecitabine for the treatment of HER2-positive advanced or metastatic breast cancer in patients who had received previous treatment (including anthracycline, taxane and trastuzumab containing regimens) and in 2010 for use in combination with letrozole for postmenopausal women with hormonal receptor positive and HER2- positive metastatic breast cancer. In contrast to trastuzumab (Herceptin), lapatinib is orally administered and it targets both HER2 and HER1 receptors. As a synthetic and oral tyrosine kinase inhibitor (TKI), it is convenient, cheaper and easier to produce than monoclonal antibodies. The recommended dosage is not dependent on body weight either. Lapatinib plasma level measurement could be an approach to tailored therapy for further optimizing the dose and prolonging this efficient therapy. New lapatinib response predictors are being evaluated. At this time, only HER2 amplification/overexpression is used to choose lapatinib therapy candidates. Further studies on concurrent HER1 fluorescent in situ hybridization (FISH)/immunohistochemistry (IHC) assessment and/or microarray analyses may produce new data on the predictive role of the HER1 (EGFR) gene/protein. PTEN loss and PIK3CA gene mutations are other markers that may predict lapatinib poor response.
- MeSH
- antitumorózní látky krev terapeutické užití MeSH
- chinazoliny krev terapeutické užití MeSH
- erbB receptory genetika MeSH
- financování organizované MeSH
- fosfohydroláza PTEN genetika MeSH
- fosfotransferasy s alkoholovou skupinou jako akceptorem genetika MeSH
- geny erbB-2 MeSH
- inhibitory proteinkinas krev terapeutické užití MeSH
- lidé MeSH
- nádory prsu farmakoterapie genetika krev MeSH
- prediktivní hodnota testů MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- chinazoliny analýza krev MeSH
- experimenty na zvířatech MeSH
- hypotonické roztoky analýza krev MeSH
- krevní tlak účinky záření MeSH
- psi MeSH
- Check Tag
- psi MeSH
- Publikační typ
- srovnávací studie MeSH
[Densitometric determination of prazosin in the plasma]
