Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
J Mass Spectrom. 2011 Oct;46(10):1039-45. doi: 10.1002/jms.1985.
E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N-methyl-naphthalene-1-carboxamide, is a novel, potent, dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors with antiangiogenic properties, now under early clinical evaluation as an anticancer agent. To investigate its clinical pharmacokinetics, a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated to measure the drug in human plasma on the basis of simple protein precipitation with methanol after addition of deuterated E-3810 as internal standard. The method requires a small volume of sample (100 µl) and is rapid and selective, allowing good resolution of peaks in 5 min. It is sensitive, precise, and accurate, with overall precision, expressed as CV%, always ≤7.1%, accuracy in the range 92.7%-104.4%, and high recovery, close to 100%. The limit of detection is 0.01 ng/ml, and the lower limit of quantitation is 2.0 ng/ml. The assay was validated in the range from the lower limit of quantitation up to 500.0 ng/ml. This is the first method developed and validated for analyzing E-3810 in human plasma. The method has been successfully applied to study E-3810 pharmacokinetics in cancer patients with solid tumors who are receiving daily oral doses of the drug during the phase I trial.
E-3810，6-[[7-[(1-氨基环丙基)甲氧基]-6-甲氧基-4-喹啉基]氧基]-N-甲基-萘-1-羧酰胺，是一种新型、强效的血管内皮生长因子和成纤维细胞生长因子受体双重抑制剂，具有抗血管生成特性，目前正在早期临床评估阶段，作为一种抗癌药物。为了研究其临床药代动力学，开发并验证了一种高效液相色谱-串联质谱法，该方法基于甲醇简单的蛋白沉淀，加入氘代 E-3810 作为内标后，可在人血浆中测定药物。该方法需要的样品量较小（100 µl），快速且具有选择性，可在 5 分钟内实现良好的峰分离。该方法灵敏度高、精确、准确，总精密度（以 CV%表示）始终≤7.1%，准确度在 92.7%-104.4%范围内，回收率高，接近 100%。检测限为 0.01 ng/ml，定量下限为 2.0 ng/ml。该检测方法在从定量下限到 500.0 ng/ml 的范围内进行了验证。这是首次开发并验证用于分析人血浆中 E-3810 的方法。该方法已成功应用于接受 I 期临床试验中每日口服该药物的实体瘤癌症患者的 E-3810 药代动力学研究。
