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LC-MS/MS method for quantitation of the CK2 inhibitor silmitasertib (CX-4945) in human plasma, CSF, and brain tissue, and application to a clinical pharmacokinetic study in children with brain tumors.
Journal of Chromatography B ( IF 2.8 ) Pub Date : 2020-06-23 , DOI: 10.1016/j.jchromb.2020.122254
Bo Zhong 1 , Olivia Campagne 1 , Ralph Salloum 2 , Teresa Purzner 3 , Clinton F Stewart 1
Affiliation  

Silmitasertib (CX-4945) as a potent and selective inhibitor of CK2 exhibited promising in vitro and in vivo anti-cancer activity. An assay employing cation-exchange solid phase extraction (SPE) followed by LC-MS/MS analysis was successfully developed and validated for the quantitation of silmitasertib in human plasma, brain tissue, and human cerebrospinal fluid (CSF). Reverse phase chromatographic separation was achieved using Synergi™ hydro-RP column (4 μm, 75 × 2.0 mm) and gradient elution with 5 mM ammonium formate aqueous solution (pH 6.5) as mobile phase A and 0.1% formic acid in acetonitrile as mobile phase B. Multiple reaction monitoring (MRM) transition of m/z 350.2 → 223.2 and m/z 316.2 → 223.2 were chosen for detection of silmitasertib and internal standard (CX-4786) respectively. Since silmitasertib concentration in patient plasma is expected to be in a wide range due to the study design, two calibration curves with range 0.2–125 ng/ml and 32–20,000 ng/ml were established. A different curve ranging from 2 to 40 ng/g was used for measurement of silmitasertib in brain tissue, while another calibration curve ranging from 0.2 to 20 ng/ml was established for CSF. All these calibration curves corresponding to different matrices showed good linearity (R2 > 0.99) over the concentration range. This assay demonstrated excellent precision below 15% and accuracies between 85% and 115% within–day and between–day for all the concentration levels in each matrix. This assay was also validated for each matrix for selectivity, sensitivity, matrix effects, recovery, and stability. We applied the validated method to the analysis of plasma silmitasertib for a clinical study.



中文翻译:

LC-MS/MS 方法定量人血浆、CSF 和脑组织中的 CK2 抑制剂 silmitasertib (CX-4945),并应用于儿童脑肿瘤的临床药代动力学研究。

Silmitasertib (CX-4945) 作为 CK2 的一种有效且选择性的抑制剂,在体外和体内表现出良好的抗癌活性。采用阳离子交换固相萃取 (SPE) 和 LC-MS/MS 分析的测定方法已成功开发并验证,可用于定量人血浆、脑组织和人脑脊液 (CSF) 中的 silmitasertib。使用 Synergi™ Hydro-RP 柱(4 μm,75 × 2.0 mm)和以 5 mM 甲酸铵水溶液(pH 6.5)作为流动相 A 和 0.1% 甲酸乙腈溶液作为流动相的梯度洗脱实现反相色谱分离B. m / z 350.2 → 223.2 和m / z 的多反应监测 (MRM) 跃迁选择 316.2 → 223.2 分别检测 silmitasertib 和内标 (CX-4786)。由于研究设计,预计患者血浆中 silmitasertib 的浓度范围很广,因此建立了两条校准曲线,范围为 0.2-125 ng/ml 和 32-20,000 ng/ml。范围为 2 至 40 ng/g 的不同曲线用于测量脑组织中的 silmitasertib,而另一条范围为 0.2 至 20 ng/ml 的校准曲线用于 CSF。所有这些对应于不同基质的校准曲线都显示出良好的线性(R 2 > 0.99) 在浓度范围内。对于每种基质中的所有浓度水平,该测定在日内和日间显示了低于 15% 的出色精密度和 85% 至 115% 之间的准确度。该测定还针对每种基质的选择性、灵敏度、基质效应、回收率和稳定性进行了验证。我们将经过验证的方法应用于分析血浆 silmitasertib 以进行临床研究。

更新日期:2020-06-29
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