Determination of regorafenib (BAY 73-4506) and its major human metabolites BAY 75-7495 (M-2) and BAY 81-8752 (M-5) in human plasma by stable-isotope dilution liquid chromatography-tandem MS
Determination of regorafenib (BAY 73-4506) and its major human metabolites BAY 75-7495 (M-2) and BAY 81-8752 (M-5) in human plasma by stable-isotope dilution liquid chromatography-tandem MS
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DOI：
10.4155/bio.14.52
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发表时间：
2014-07-01
期刊：
影响因子：
1.8
通讯作者：
Kaiser, Michael
中科院分区：
文献类型：
--
作者：
Hafner, Frank-Thorsten;Werner, Daniel;Kaiser, Michael
背景：Regorafenib （BAY 73-4506，商业名称Stivarga (R)）是由德国拜耳制药公司（Bayer Pharma AG）开发的口服多激酶抑制剂，靶向血管生成、基质和致癌受体酪氨酸激酶。建立了一种同位素稀释液相色谱-串联质谱法，用于同时测定锂-肝素化人血浆中瑞非尼及其两种主要代谢物BAY 75-7495 （M-2）和BAY 81-8752 （M-5）。结果：蛋白沉淀在三重四极串联质谱仪上进行分析。所有分析物的验证浓度范围为2.00（定量下限）~ 2000 μ g/l。在四种潜在药物存在的情况下，证明了选择性和特异性。测定结果的准确度和精密度变异系数分别为91.2% ~ 105% （M-5的定量限）和3.59 ~ 14.1%。结论：该方法选择性强，特异性强，灵敏度高，重现性好，适用于大量样品的分析。该方法的性能符合现行生物分析方法验证指南。
Background: Regorafenib (BAY 73-4506, commercial name Stivarga (R)) is an oral multikinase inhibitor developed by Bayer Pharma AG (Germany) that targets angiogenic, stromal and oncogenic receptor tyrosine kinases. An isotope dilution liquid chromatography-tandem mass spectrometry method has been developed and validated for the simultaneous determination of regorafenib and its two major metabolites BAY 75-7495 (M-2) and BAY 81-8752 (M-5) in lithium-heparinized human plasma. Results: Analysis was performed after protein precipitation on a triple-quadrupole tandem mass spectrometer. The validated concentration range was from 2.00 (lower limit of quantitation) to 2000 mu g/l for all the analytes. Selectivity and specificity in the presence of four potential comedications were demonstrated. Interassay accuracy and precision coefficient of variation ranged from 91.2% (at LLOQ of M-5) to 105% and 3.59 to 14.1%, respectively. Conclusion: The method proved to be selective, specific, sufficiently sensitive, highly reproducible and robust for the analysis of large numbers of samples. The method performance met current guidelines on bioanalytical method validation.