液相色谱-高分辨率质谱法定量单甲基澳瑞他汀E（MMAE）及其临床前药代动力学。,Biomedical Chromatography

当前位置： X-MOL 学术 › Biomed. Chromatogr. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

液相色谱-高分辨率质谱法定量单甲基澳瑞他汀E（MMAE）及其临床前药代动力学。
Biomedical Chromatography ( IF 1.8 ) Pub Date : 2020-04-17 , DOI: 10.1002/bmc.4855
Byeong Ill Lee ₁ , Min-Ho Park ₁ , Jangmi Choi ₁ , Seok-Ho Shin ₁ , Jin-Ju Byeon ₁ , Yuri Park ₁ , Young G Shin ₁

Affiliation

MMAE是一种有效的抗有丝分裂药物，用作抗体-药物偶联物的有效载荷，在临床前和临床研究中显示出对多种淋巴瘤，白血病和实体瘤的有效活性。液相色谱-高分辨率质谱法用于定量MMAE及其临床前药代动力学。该方法包括使用乙腈（ACN）进行蛋白质前处理和液相色谱–四极–飞行时间–串联质谱（LC-qTOF-MS / MS）分析，以阳离子模式进行蛋白质沉淀。二次回归（加权1 /浓度²），方程y = ax ² + bx + c用于拟合MMAE在1.01-2200 ng / mL浓度范围内的校准曲线。鉴定运行符合QC样品的±25％准确度和精密度值的接受标准。回收率为42.84％。确定了5倍稀释液的稀释液完整性，准确度和精密度在±25％范围内。稳定性结果表明，MMAE在以下条件下是稳定的：短期（4小时），长期（4周），冻融（3个周期）和制备后的稳定性（12小时）。该合格方法已成功应用于大鼠MMAE的药代动力学研究，作为临床前动物模型。PK结果表明MMAE具有中等的CL和较低的BA，此外，这些结果将有助于全面了解MMAE的PK特性以及将来开发ADC。

"点击查看英文标题和摘要"

Liquid chromatography-high resolution mass spectrometric method for the quantification of monomethyl auristatin E (MMAE) and its preclinical pharmacokinetics.

MMAE is a potent antimitotic drug used as payload of an antibody‐drug conjugate which shows potent activity in preclinical and clinical studies against a range of lymphomas, leukemia and solid tumors. Liquid chromatography‐high resolution mass spectrometric method was developed for the quantification of MMAE and its preclinical pharmacokinetics. The method consisted of protein precipitation using acetonitrile (ACN) for sample preparation and liquid chromatography – quadrupole – time‐of‐flight – tandem mass spectrometry (LC‐qTOF‐MS/MS) analysis in the positive ion mode. A quadratic regression (weighted 1/concentration²), with an equation y = ax² + bx + c, was used to fit calibration curves over the concentration range of 1.01–2,200 ng/mL for MMAE. The qualification run met the acceptance criteria of ±25% accuracy and precision values for QC samples. Recovery was 42.84%. The dilution integrity was determined for 5‐fold dilution and the accuracy and precision ranged within ±25%. The stability results indicated that MMAE was stable for the following conditions: short‐term (4 h), long‐term (4 weeks), freeze/thaw (3 cycles) and post‐preparative stability (12 h). This qualified method was successfully applied to a pharmacokinetic study of MMAE in rat as a preclinical animal model. The PK results suggest that MMAE has moderate CL and low BA.Also, these results would be helpful in having a comprehensive understanding of the PK characteristics of MMAE and developing ADC in future.

更新日期：2020-04-17

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南