Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
DMPK Department, Centaurus Biopharma Co., Ltd., Beijing 100195, China.
J Pharm Biomed Anal. 2018 May 10;153:1-8. doi: 10.1016/j.jpba.2018.01.042. Epub 2018 Jan 31.
CT-707, a mutant-selective inhibitor of an important cancer target, anaplastic lymphoma kinase (ALK), is designed to be a targeted therapeutic agent for non-small cell lung cancer (NSCLC) patients harboring ALK active and crizotinib resistant mutations. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of CT-707 and its two metabolites (M1 and M2) in human plasma. The samples were purified by solid phase extraction (SPE) and separated on a BEH C18 column (2.1 × 50 mm, 1.7 μm). Electrospray ionization (ESI) in positive ion mode and multiple reactions monitoring (MRM) were used to monitor the ion transitions at m/z 636.4 → 413.3, 594.4 → 494.4, 622.5 → 536.4, respectively. The results indicated that the method had excellent sensitivity and selectivity. The linear range covered from 2 to 500 ng/mL for CT-707and from 1 to 100 ng/mL for M1 and M2. Intra-run and inter-run precisions (in terms of %RSD) were all <15% and the accuracies (in terms of %RE) were within the range of ±15%. The lower limit of quantification (LLOQ), matrix effect, extraction recovery, stability, dilution test and carryover test were also validated and satisfied with the criteria of validation. Finally, the method was successfully applied to a phase I clinical study of ALK-positive advanced NSCLC patients after an oral administration of CT-707.
CT-707 是一种针对间变性淋巴瘤激酶（ALK）这一重要癌症靶点的突变体选择性抑制剂，旨在成为携带 ALK 激活和克唑替尼耐药突变的非小细胞肺癌（NSCLC）患者的靶向治疗药物。本文建立并验证了一种灵敏、快速的超高效液相色谱-串联质谱法（UPLC-MS/MS），用于测定人血浆中的 CT-707 及其两种代谢产物（M1 和 M2）。样品经固相萃取（SPE）净化，采用 BEH C18 柱（2.1×50mm，1.7μm）分离。电喷雾离子化（ESI）正离子模式和多反应监测（MRM）用于监测 m/z 636.4→413.3、594.4→494.4、622.5→536.4 的离子跃迁。结果表明，该方法具有良好的灵敏度和选择性。CT-707 的线性范围为 2500ng/mL，M1 和 M2 的线性范围为 1100ng/mL。批内和批间精密度（以%RSD 表示）均<15%，准确度（以%RE 表示）在±15%范围内。定量下限（LLOQ）、基质效应、提取回收率、稳定性、稀释稳定性和交叉污染均通过验证，符合验证标准。最后，该方法成功应用于口服 CT-707 后 ALK 阳性晚期 NSCLC 患者的 I 期临床试验。
