AMG 510 is the first‐in‐class KRAS^G12C inhibitor, currently in phase 2 clinical trials as an orphan drug to treat non‐small cell lung cancer patients. We developed and validated a sensitive, selective, and high‐throughput HPLC‐MS/MS method for the quantitation of AMG 510 in mouse plasma per the regulatory guideline of the US Food and Drug and Administration. AMG 510 and the IS (MRTX‐1257) were extracted from mouse plasma using tert‐butyl methyl ether and chromatographed using an isocratic mobile phase (0.2% formic acid:acetonitrile; 25:75, v/v) at a flow rate of 0.65 mL/min on an Atlantis dC₁₈ column. AMG 510 and the IS eluted at ~0.95 and 0.73 min, respectively. AMG 510 and the IS were detected by positive electrospray ionization in multiple reaction monitoring using transition pair (Q1 → Q3) m/z 561.1 → 134.1 and m/z 566.5 → 98.2, respectively. Excellent linearity was achieved in the concentration range of 1.08–5040 ng/mL (r > 0.0996). No matrix effect and carryover were observed. Intra‐ and inter‐day accuracies and precisions were within the acceptance range. AMG 510 was demonstrated to be stable under the tested storage conditions. This novel method has been applied to a pharmacokinetic study in mice.

中文翻译：

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经过验证的HPLC-MS / MS方法可定量测定小鼠血浆中的KRAS G12C抑制剂AMG 510及其在小鼠体内药代动力学研究中的应用

AMG 510是一流的KRAS ^G12C抑制剂，目前正在作为治疗非小细胞肺癌患者的孤儿药物进行2期临床试验。我们根据美国食品药品管理局的监管指南，开发并验证了一种灵敏，选择性高通量的HPLC-MS / MS方法，用于定量测定小鼠血浆中的AMG 510。使用叔丁基甲基醚从小鼠血浆中提取AMG 510和IS（MRTX-1257），并使用等度流动相（0.2％甲酸：乙腈; 25：75，v / v）进行色谱分离，流速为0.65在Atlantis dC ₁₈上的mL / min柱子。AMG 510和IS分别在〜0.95和0.73分钟时洗脱。在多反应监测中，分别使用过渡对（Q1→Q3）m / z 561.1→134.1和m / z 566.5→98.2，通过正电喷雾电离检测AMG 510和IS 。在1.08–5040 ng / mL的浓度范围内，可获得出色的线性（r  > 0.0996）。没有观察到基质效应和残留。日内和日间精度和精度均在接受范围内。事实证明，AMG 510在测试的存储条件下稳定。该新方法已应用于小鼠的药代动力学研究。