Development and Validation of an LC-MS/MS Method to Quantify Gilteritinib and Its Clinical Application in Patients With FLT3 Mutation-Positive Acute Myelogenous Leukemia
Development and Validation of an LC-MS/MS Method to Quantify Gilteritinib and Its Clinical Application in Patients With FLT3 Mutation-Positive Acute Myelogenous Leukemia
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定量 Gilteritinib 的 LC-MS/MS 方法的开发和验证及其在 FLT3 突变阳性急性髓性白血病患者中的临床应用
DOI：
10.1097/ftd.0000000000000971
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发表时间：
2022
影响因子：
2.5
通讯作者：
Ieiri I.
中科院分区：
文献类型：
--
作者：
Zhang M;Tajima S;Suetsugu K;Hirota T;Tsuchiya Y;Yamauchi T;Yoshimoto G;Miyamoto T;Egashira N;Akashi K;Ieiri I.
背景：Gilteritinib是一种新型口服酪氨酸激酶抑制剂，用于治疗具有FMS样酪氨酸激酶3（FLT3）突变的急性髓系白血病（AML）。吉特替尼的治疗药物监测（TDM）对于改善临床结果和确保安全性非常重要。因此，本研究旨在开发一种利用液相色谱-串联质谱法定量人血浆中吉特替尼的简化方法。方法：采用Acquity BEH C18柱（50 mm×2.1 mm，1.7 μm）和0.1%甲酸的水（A）和乙腈（B）梯度洗脱进行液相色谱分析。使用岛津串联质谱仪通过正离子模式下的多反应监测进行检测。 结果：所开发的方法能够在 4 分钟内对 gilteritinib 进行定量，并通过评估选择性、校准曲线（10–1000 ng/mL，r 2> 0.99）、定量下限（LLOQ）、准确性（总体偏倚− 4.2% 至 1.9%）、精密度（日内）进行验证。 CV≤ 7.9%；日间 CV≤ 13.6%)、残留、回收率、基质效应、稀释完整性和稳定性符合美国食品和药物管理局 (FDA) 指南。该方法成功应用于 3 名 AML 患者的 gilteritinib 谷浓度的 TDM。结论：所开发的方法符合 FDA 指南标准，并且可以轻松实施，以促进临床环境中接受 gilteritinib 的患者的 TDM。
Background:Gilteritinib, a novel oral tyrosine kinase inhibitor, is used to treat acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. Therapeutic drug monitoring (TDM) of gilteritinib is important for improving clinical outcomes and ensuring safety. Therefore, this study aimed to develop a simplified method for quantifying gilteritinib in human plasma using liquid chromatography–tandem mass spectrometry.Methods:Liquid chromatography was performed by using an Acquity BEH C18 column (50 mm× 2.1 mm, 1.7 μm) and a gradient elution with 0.1% formic acid in water (A) and acetonitrile (B). Detection was performed by using a Shimadzu tandem mass spectrometer through multiple reaction monitoring in the positive-ion mode.Results:The developed method enabled quantification of gilteritinib in 4 minutes and was validated by evaluating selectivity, calibration curve (10–1000 ng/mL, r 2> 0.99), a lower limit of quantification (LLOQ), accuracy (overall bias− 4.2% to 1.9%), precision (intraday CV≤ 7.9%; interday CV≤ 13.6%), carryover, recovery, matrix effect, dilution integrity, and stability according to the US Food and Drug Administration (FDA) guidelines. This method was successfully applied to the TDM of gilteritinib trough concentrations in 3 patients with AML.Conclusions:The developed method fulfilled the FDA guideline criteria and can easily be implemented to facilitate TDM in patients receiving gilteritinib in a clinical setting.