A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma

Abstract

A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma, 2015, Journal of Pharmaceutical and Biomedical Analysis, (107), [186][187][188][189][190][191][192][193][194][195] The substances were extracted using protein precipitation, separated on a BEH XBridge C18 column (100 x 2.1 mm, 1.7 µm) by gradient elution at 0.7 mL/min of acetonitrile and 5 mM ammonium acetate. The concentration was determined using a Waters Xevo triple quadrupole mass spectrometer in a multi reaction monitoring mode. The total run time was 7 minutes. Deuterated erlotinib and OSI-597 were used as internal standard for erlotinib and its metabolites respectively.Erlotinib, OSI-420 and didesmethyl erlotinib were quantified in the concentration range 25-5,000 ng/mL, 0.5-500 ng/mL and 0.15-10 ng/mL respectively. Precision and accuracy was < 14 % except for OSI-420 at LLOQ (17 %). Extraction recovery was above 89 %, 99 % and 89 % for erlotinib, OSI-420 and didesmethyl erlotinib respectively.The human liver microsomes generated 14 metabolites, three of them not previously reported.

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.…”

Recent developments in the chromatographic bioanalysis of approved kinase inhibitor drugs in oncology

“…Although more solvents can be used, these are not always compatible or less suitable for direct injection into the chromatographic system with most used separation techniques. One method to increase the efficiency of PP is the use of ice-cold PP reagent [26,84], or even cooling to -80ºC on an ethanol/dry ice bath [26]. Cold-induced denaturation of proteins is a phenomenon that is caused by a temperature-dependent interaction of nonpolar groups within the protein with water.…”

“…For a number of known active metabolites, a quantitative assay has been reported, except for O-debenzyl-lapatinib, N-desmethyl-osimertinib, hydroxy-and N-desmethylpazopanib, N-deacetyl-trametinib, and hydroxy-ruxolitinib metabolite M5 (see Table 4). One of the main reasons for the absence of metabolite quantification is the lack of commercial standards at the time of development of the assay [84]. Alternatively, papers from Vikingsson et al [133] reported quantification of the metabolites relative to their parent compound, or a related metabolite of which an analytical standard is readily available [84,132,133].…”

“…One of the main reasons for the absence of metabolite quantification is the lack of commercial standards at the time of development of the assay [84]. Alternatively, papers from Vikingsson et al [133] reported quantification of the metabolites relative to their parent compound, or a related metabolite of which an analytical standard is readily available [84,132,133]. For sunitinib, it has been demonstrated that the active metabolite is equally potent, but less dermatotoxic.…”