Simultaneous determination of erlotinib and its isomeric major metabolites in human plasma using isocratic liquid chromatography–tandem mass spectrometry and its clinical application

Abstract

This study developed a method for the simultaneous determination of erlotinib and its isomeric major metabolites, OSI-413 and OSI-420, in human plasma using an isocratic liquid chromatography-tandem mass spectrometry. Plasma specimens deproteinized with acetonitrile were separated using a 3-µm particle size octadecylsilyl column. The m/z values of the precursor and product ions for the analytes were as follows: erlotinib, 394.2/278.2; and OSI-413 and OSI-420, 380.2/278.2. The total run time was 21 min and no peaks interfering with the analytes and internal standard (d6 -erlotinib) in human plasma were observed. The calibration curves of erlotinib, OSI-413 and OSI-420 were linear over the concentration ranges of 10-3000, 2-500 and 2-100 ng/mL, respectively. The pretreatment recovery ratios were >86.1%. The intra- and inter-assay precisions and accuracies were <12.7 and 89.0-108.9% for all analytes. This validated method was applied to the determination of plasma samples in lung cancer patients receiving 150 mg of oral erlotinib. The plasma concentration ranges of erlotinib, OSI-413 and OSI-420 were 373-2354, 15.7-379 and 2.5-43.6 ng/mL, respectively. In conclusion, the present method can be helpful for evaluating the plasma exposures of erlotinib and its major isomeric metabolites in clinical settings.

Simultaneous determination of erlotinib and tamoxifen in rat plasma using UPLC–MS/MS: Application to pharmacokinetic interaction studies

“…3. Using this method, the achieved LLOQ values of both drugs were lower than those of previously reported LC-MS/MS methods for ERL [18][19][20][21][22] and TAM [26,[29][30][31][32][33][34][35][36]. These low values of LLOQ allowed the successful application of this method in the trace analysis of the two drugs in clinical studies.…”

“…With the exception of ERL which was previously determined by our research team in rat plasma samples, in combinations with gefitinib, dexamethasone, prednisolone, and ondansetron [23], the current method provided the lowest LLOQ (0.2 ng/mL) described so far for the analysis of TAM. Compared with previously published methods for the determination of ERL [18][19][20][21][22] or TAM [26,[29][30][31][32][33][34][35][36], this method was of a remarkable sensitivity. This is extremely important for trace analysis of the studied drugs and for accurate determination of terminal phase elimination during PK studies.…”

“…They include HPLC-UV [15,16], HPLC-DAD [17], HPLC-MS/MS [18][19][20][21], and UPLC-MS/MS [22,23]. Also, TAM has been analyzed in biological matrices using numerous liquid chromatographic techniques, namely HPLCfluorimetry [24][25][26], HPLC-DAD [27], HPLC-UV [28], HPLC-MS/MS [26,[29][30][31][32], and UPLC-MS/MS [33][34][35][36].…”

A Rapid and Simple UHPLC-UV Method for Quantitative Determination of Erlotinib and Its Active Metabolite OSI-420 in Human Serum, and Its Application in a Non-Small Cell Lung Cancer Patient

“…1 (C)), OSI-420 and erlotinib with retention times of 1.1 and 2.2 min, respectively, could be separated from other peaks. Previous studies demonstrated that OSI-413 (desmethyl erlotinib), an isomeric metabolite of OSI-420, was observed between the retention times of OSI-420 and erlotinib in reversed-phase HPLC [16,17]. In those studies, the peak area of OSI-413 was larger than that of OSI-420.…”

“…Several analytical methods have been developed using liquid chromatography-tandem mass spectrometry (LC/MS/MS) [11][12][13][14][15][16][17] or high-performance liquid chromatography with ultraviolet detection (HPLC-UV) [3,18,19] to determine the concentrations of erlotinib and/or OSI-420 in human biological samples. LC/MS/MS methods are highly selective and sensitive, but due to their cost and complexity, they are not available in most hospital laboratories.…”