Kruithof Paul D, de Beer Yvo M, Gulikers Judith L, Stolk Leo M L, Hendriks Lizza E L, Croes Sander, van Geel Robin M J M
Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, AZ, Maastricht, the Netherlands; CARIM School for Cardiovascular Disease, Maastricht University Medical Center+, MD, Maastricht, the Netherlands.
Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, AZ, Maastricht, the Netherlands.
J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Dec 1;1231:123918. doi: 10.1016/j.jchromb.2023.123918. Epub 2023 Nov 7.
Recently, two small molecular inhibitors (SMIs) -adagrasib and sotorasib- have been introduced for targeting Kirsten rat sarcoma (KRAS) p.G12C mutations in patients with non-small cell lung cancer (NSCLC). In order to support pharmacokinetic research as well as clinical decision making, we developed and validated a simple and accurate liquid chromatography-tandem mass spectrometry method for the multiplexed quantification of adagrasib and sotorasib. This assay was co-validated with the quantification for brigatinib, lorlatinib, pralsetinib and selpercatinib. Methanol was used for single-step protein precipitation. Chromatographic separation was performed using an Acquity® HSS C18 UPLC column, with an elution gradient of ammonium formate 0.1 % / in water and acetonitrile. In K2-EDTA plasma, adagrasib was found to be stable for at least seven days at room temperature and 4 °C, and at least 3 months at -80 °C. Sotorasib was found to be stable for at least three days at room temperature, seven days at 4 °C and at least 3 months at -80 °C. The method was validated over a linear range of 80-4000 ng/mL for adagrasib and 25-2500 ng/mL for sotorasib. The assay is therefore well-equipped for determining plasma concentrations in clinical practice.
最近，两种小分子抑制剂（SMIs）——阿达格拉西布和索托拉西布——已被用于治疗非小细胞肺癌（NSCLC）患者的 Kirsten 大鼠肉瘤（KRAS）p.G12C 突变。为了支持药代动力学研究以及临床决策，我们开发并验证了一种简单准确的液相色谱-串联质谱法，用于对阿达格拉西布和索托拉西布进行多重定量分析。该分析方法与布加替尼、洛拉替尼、普拉替尼和塞尔帕替尼的定量分析共同进行了验证。使用甲醇进行一步式蛋白沉淀。采用 Acquity® HSS C18 UPLC 柱进行色谱分离，洗脱梯度为 0.1%甲酸/水和乙腈。在 K2-EDTA 血浆中，发现阿达格拉西布在室温下和 4℃至少稳定 7 天，在-80℃至少稳定 3 个月。索托拉西布在室温下至少稳定 3 天，在 4℃稳定 7 天，在-80℃至少稳定 3 个月。该方法在阿达格拉西布 80 - 4000 ng/mL 和索托拉西布 25 - 2500 ng/mL 的线性范围内得到验证。因此，该分析方法非常适合在临床实践中测定血浆浓度。
