Laboratoire de Pharmacocinétique, Faculté de Pharmacie de Marseille, SMARTc, Simulation and Modeling Adaptative Response for Therapeutics in Cancer, 27 Bd Jean Moulin, 13385, Marseille, France.
Faculté de Pharmacie de Marseille, COMPO, CRCM Inserm UMR 1068 & INRIA Sophia Antipolis, 27 Boulevard Jean-Moulin, 13385, Marseille, France.
Cancer Chemother Pharmacol. 2023 Mar;91(3):231-238. doi: 10.1007/s00280-023-04505-y. Epub 2023 Mar 1.
Azacitidine (Vidaza®, AZA) is a mainstay for treating acute myeloid leukemia (AML) in patients unfit for standard induction and other myelodysplastic syndromes (MDS). However, only half of the patients usually respond to this drug and almost all patients will eventually relapse. Predictive markers for response to AZA are yet to be identified. AZA is metabolized in the liver by a single enzyme, cytidine deaminase (CDA). CDA is a ubiquitous enzyme coded by a highly polymorphic gene, with subsequent great variability in resulting activities in the liver. The quantitative determination of AZA in plasma is challenging due the required sensitivity and because of the instability in the biological matrix upon sampling, possibly resulting in erratic values.
We have developed and validated following EMA standards a simple, rapid, and cost-effective liquid chromatography-tandem mass spectrometry method for the determination of azacitidine in human plasma.
After a simple and rapid precipitation step, analytes were successfully separated and quantitated over a 5-500 ng/mL range. The performance and reliability of this method were tested as part of an investigational study in MDS/AML patients treated with standard azacitidine (75 mg/m for 7 days a week every 28 days).
Overall, this new method meets the requirements of current bioanalytical guidelines and could be used to monitor drug levels in MDS/AML patients.
阿扎胞苷（Vidaza®，AZA）是治疗不适合标准诱导治疗的急性髓系白血病（AML）和其他骨髓增生异常综合征（MDS）的主要药物。然而，通常只有一半的患者对这种药物有反应，几乎所有患者最终都会复发。预测 AZA 反应的生物标志物尚未确定。AZA 在肝脏中由一种酶，胞苷脱氨酶（CDA）代谢。CDA 是一种广泛存在的酶，由一个高度多态性的基因编码，导致肝脏中酶活性的巨大变异性。由于所需的灵敏度以及采样时生物基质的不稳定性，导致 AZA 在血浆中的定量测定具有挑战性，可能导致值不稳定。
我们根据 EMA 标准开发并验证了一种简单、快速且具有成本效益的液相色谱-串联质谱法，用于测定人血浆中的阿扎胞苷。
经过简单快速的沉淀步骤，分析物在 5-500ng/mL 范围内成功分离和定量。作为 MDS/AML 患者用标准 AZA（75mg/m，每周 7 天，每 28 天 1 个疗程）治疗的研究的一部分，对该方法的性能和可靠性进行了测试。
总的来说，这种新方法满足当前生物分析指南的要求，可用于监测 MDS/AML 患者的药物水平。
