Abstract
This study was designed to develop and validate a UPLC-MS/MS method for quantification of neratinib in human plasmsa. Neratinib is an irreversible tyrosine kinase inhibitor against the pan-ErbB (ErbB-1, -2, -4) receptor. UPLC-MS/MS is an excellent analytical methodology for rapid biomedical analysis, decreasing the time for analysis and maintaining good efficiency. Crizotinib was used as internal standard (IS). Samples where extracted by plasma protein precipitation (PPT) procedure with acetonitrile and methanol and analysis was performed on a C 18 Acquity UPLCBEH TM column. The ion transitions where recorded in positive ion multiple reaction monitoring mode m/z 557.51®112.17 for neratinib and m/z 450.0®260.0 for IS. The mobile phase used was methanol:water: formic acid (70:30:0.1 %, v/v/v) with a flow rate of 0.3mL min –1 . The linearity of the assay was found to be 4–500 ngmL –1 for neratinib in human plasma with lower limit of quatification of 4 ngmL –1 . The intra- and inter-assay precision relative standard deviations did not exceed 10.99 and mean extraction recovery was found to be 69.12 ± 3.58. KEYWORDS Neratinib, UPLC, LC-MS/MS, pharmacokinetic study, human plasma.
Highlights
In controlling critical cellular activities such as the cell migration, cell cycle, cell survival and metabolism, cell differentiation and proliferation, the receptor tyrosine kinase plays a very important role.[1]
In various cancers hyperactivation of epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases was observed and elevated levels of ErbB-2 and poor prognosis in 30 % cases of breast cancer is correlated with over-expression.[2,3,4]
Human plasma was obtained from normal healthy volunteers at King Khalid University Hospital (Riyadh, Saudi Arabia), and ethical approval was obtained from the institutional review board of the King Khalid University Hospital
Summary
In controlling critical cellular activities such as the cell migration, cell cycle, cell survival and metabolism, cell differentiation and proliferation, the receptor tyrosine kinase plays a very important role.[1] In various cancers hyperactivation of epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases was observed and elevated levels of ErbB-2 and poor prognosis in (approximately) 30 % cases of breast cancer is correlated with over-expression.[2,3,4] Monotherapy with transtuzumab[4,5] which is the standard treatment for ErbB-2-positive breast cancer provides only 15 % response rates, where as a combination of transtuzumab with paclitaxel or chemotherapy increases the success rate to 41 % and 50 %, respectively.[5,6] The most common problem with transtuzumab is the development of resistance.[7] Neratinib (NTB) is a low molecular weight, potent, irreversible inhibitor of EGFR, HER2 and HER4 tyrosine kinase activity[2,8,9,10] and has exhibited promising preclinical activity alone or in with combination pactitaxel or transtuzumab against HER2-overexpressing cell lines.[8,11,12,13] NTB is currently undergoing several phase three clinical trials.[14,15]
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