A Validated RP-HPLC Method for the Estimation of Lapatinib in Tablet Dosage form using Gemcitabine Hydrochloride as an Internal Standard

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. ×250 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±0.05 and 6.10±0.05 min, respectively. The method produced linear responses in the concentration range of 2-60 μg/ml of lapatinib. The limit of detection and limit of quantitation were 0.265 and 0.884 μg/ml, respectively.     

Her2 positive breast cancer: practices

The molecular classification of Perou and Sørlie breast tumors has to streamline, systematize and make effective use of targeted therapies against specific molecular subtypes, including breast HER2 positive. Trastuzumab and lapatinib are currently the two therapies targeting HER2, which have demonstrated their effectiveness in clinical practice. This literature review aims to make the data points on pertinent and useful data for physicians in daily     

Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study

BackgroundBreast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood–tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy.MethodsStudy patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m²) 2–3 h before surgery or 2–5 doses of lapatinib (1250 mg) daily, the last dose 2–3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry.ResultsTwelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 µM. A high variability (0.19–9.8) was noted for lapatinib BCBM-to-serum ratio.ConclusionsThis is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system.Trial registration ID: {"type":"clinical-trial","attrs":{"text":"NCT00795678","term_id":"NCT00795678"}}NCT00795678.     

Impact of Her‐2‐Targeted Therapy on Overall Survival in Patients With Her‐2 Positive Metastatic Breast Cancer

Upon disease progression on trastuzumab‐based therapy, patients with HER‐2 positive metastatic breast cancer (MBC) may switch to lapatinib or continue on trastuzumab. We aimed to assess the impact of both strategies on overall survival (OS) in all patients treated for HER‐2 positive MBC at the Medical University Vienna from 1999 until 2009. A total of 201 patients were identified from a breast cancer data base. Of these 115 (57.2%) received multiple lines of trastuzumab‐based therapy, whereas 58 (28.9%) were treated with a single line. A control group of 28 patients (13.9%) had never received trastuzumab as they were treated before 1999, when trastuzumab was registered. OS from diagnosis of metastatic disease was defined as primary study endpoint. Trastuzumab significantly prolonged OS in HER‐2 positive MBC (41 versus 13 months; p < 0.001). Administration of multiple lines further improved OS; this, however, did not reach statistical significance (47 versus 28 months; p = 0.069). Positive estrogen receptor (ER) status (HR 1.6; 95% CI 1.13–2.27) was associated with better outcome compared to negative estrogen receptor status (p = 0.02). Addition of lapatinib did not improve OS significantly in patients with prior trastuzumab‐based therapy (62 versus 47 months; p = n.s.). Patients receiving lapatinib after diagnosis of BM, however, experienced an improvement of OS (22 versus 5 months; p = 0.022). Trastuzumab improves OS in patients with HER‐2 positive MBC with further nonsignificant improvement when administered in multiple lines. Lapatinib did not further improve OS in the entire population; however, lapatinib might improve OS in patients with BM.     

Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies

Background:

We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics.

Methods:

Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m⁻²)/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate.

Results:

Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months).

Conclusions:

Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m⁻² in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.     

冷冻干燥法制备甲苯磺酸拉帕替尼固体分散体及其大鼠药动学评价

目的用冷冻干燥技术制备甲苯磺酸拉帕替尼固体分散体,以提高其生物利用度。方法以PVPS630和soluplus^■为载体,采用冷冻干燥法制备甲苯磺酸拉帕替尼固体分散体,通过SEM、DSC、XRPD等手段对固体分散体进行表征,通过表观溶解度、溶出度和大鼠体内药动学测定,评价固体分散体的增溶效果和生物利用度的改善情况。结果在相同药载比的条件下,PVPS630组的溶出度和表观溶解度均优于soluplus^■组。DSC、XRPD、SEM等表征结果显示,PVPS630为载体的固体分散体中,原料均以非晶态存在,而以soluplus^■为载体时,只有药载比为1∶3条件下,原料才呈现非晶态特征。大鼠药动学测定结果表明,固体分散体(甲苯磺酸拉帕替尼-PVPS630为1∶3)较上市药品AUC提高23.64%。结论载体PVPS630与甲苯磺酸拉帕替尼的相容性更理想;固体分散技术有助于本品提高生物利用度。