Zhang Mengyu, Tajima Soichiro, Suetsugu Kimitaka, Hirota Takeshi, Tsuchiya Yuichi, Yamauchi Takuji, Yoshimoto Goichi, Miyamoto Toshihiro, Egashira Nobuaki, Akashi Koichi, Ieiri Ichiro
Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan.
Ther Drug Monit. 2022 Aug 1;44(4):592-596. doi: 10.1097/FTD.0000000000000971.
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.
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.
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.
The developed method fulfilled the FDA guideline criteria and can easily be implemented to facilitate TDM in patients receiving gilteritinib in a clinical setting.
吉瑞替尼是一种新型口服酪氨酸激酶抑制剂，用于治疗伴有FMS样酪氨酸激酶3（FLT3）突变的急性髓系白血病（AML）。吉瑞替尼的治疗药物监测（TDM）对于改善临床疗效和确保安全性至关重要。因此，本研究旨在开发一种使用液相色谱-串联质谱法定量测定人血浆中吉瑞替尼的简化方法。
采用Acquity BEH C18色谱柱（50 mm×2.1 mm，1.7μm）进行液相色谱分析，流动相为含0.1%甲酸的水（A）和乙腈（B），采用梯度洗脱。使用岛津串联质谱仪在正离子模式下通过多反应监测进行检测。
所开发的方法能够在4分钟内定量测定吉瑞替尼，并根据美国食品药品监督管理局（FDA）指南，通过评估选择性、校准曲线（10 - 1000 ng/mL，r²>0.99）、定量下限（LLOQ）、准确度（总体偏差-4.2%至1.9%）、精密度（日内变异系数≤7.9%；日间变异系数≤13.6%）、残留、回收率、基质效应、稀释完整性和稳定性对该方法进行了验证。该方法成功应用于3例AML患者吉瑞替尼谷浓度的TDM。
所开发的方法符合FDA指南标准，在临床环境中可轻松实施，以促进接受吉瑞替尼治疗患者的TDM。
