An LC-MS/MS Method for Absolute Quantification of Nivolumab in Human Plasma: Application to Clinical Therapeutic Drug Monitoring
An LC-MS/MS Method for Absolute Quantification of Nivolumab in Human Plasma: Application to Clinical Therapeutic Drug Monitoring
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DOI：
10.1097/ftd.0000000000000558
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发表时间：
2018-12-01
影响因子：
2.5
通讯作者：
Fukushima, Shoji
中科院分区：
文献类型：
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作者：
Irie, Kei;Okada, Akira;Fukushima, Shoji
背景：纳武单抗是一种完全人源化的 IgG4 单克隆抗体，靶向程序性死亡 1 (PD-1) 受体，破坏 PD-1 介导的信号传导并恢复抗肿瘤免疫。本研究的目的是开发一种采用液相色谱-串联质谱 (LC-MS/MS) 的纳武单抗定量方法，并评估其在临床治疗药物监测中的应用。 方法：使用 rProtein A 树脂从人血浆中纯化纳武单抗，然后用胰蛋白酶消化。通过三重四极杆质谱法检测到 AS-GITFSNSGMHWVR 肽（多反应监测转变：m/z 550.6 -> 661.4）作为纳武单抗的替代肽。血浆样本 (126) 采集自 14 名接受纳武单抗临床给药方案的非小细胞肺癌患者。基于先前报道的纳武单抗群体药代动力学 (PPK) 模型，使用 Phoenix NLME 软件（版本 7.0，Certara，St. Louis，MO）对药代动力学数据进行分析。结果：纳武单抗在人血浆中被选择性检测到，线性范围为 5-200 mcg/mL（R-2 = 0.99）。准确度以及日内和日间不精密度在 5（定量下限）、10（低）、80（中）和 160（高）mcg/mL 质量控制值的 +/- 15% 范围内。使用 LC-MS/MS 测量的纳武单抗浓度与之前报道的 PPK 模型一致，并且可以使用贝叶斯方法从单个谷浓度充分预测药代动力学参数。结论：成功开发并验证了使用 LC-MS/MS 的纳武单抗绝对定量方法。结合PPK分析，该方法应可用于临床实践中nivolumab的治疗药物监测。
Background: Nivolumab is a fully humanized IgG4 monoclonal antibody that targets the programmed death-1 (PD-1) receptor, disrupting PD-1-mediated signaling and restoring antitumor immunity. The objective of this study was to develop a nivolumab quantification method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and to evaluate its application in clinical therapeutic drug monitoring.Methods: Nivolumab was purified from human plasma using rProtein A resin and then digested with trypsin. The AS-GITFSNSGMHWVR peptide (multiple reaction monitoring transition: m/z 550.6 -> 661.4) was detected as a surrogate peptide of nivolumab by triple quadrupole mass spectrometry. Plasma samples (126) were collected from 14 patients with non-small cell lung cancer who were undergoing clinical dosing regimen with nivolumab. The pharmacokinetic data were analyzed using Phoenix NLME software (Version 7.0, Certara, St. Louis, MO) based on a previously reported population pharmacokinetics (PPK) model of nivolumab.Results: Nivolumab was selectively detected in human plasma and the linear range was 5-200 mcg/mL (R-2 = 0.99). The accuracy and intraday and interday imprecision were within +/- 15% of the quality control values of 5 (lower limit of quantification), 10 (low), 80 (medium), and 160 (high) mcg/mL. The nivolumab concentrations measured using LC-MS/MS were consistent with those of previously reported PPK models, and the pharmacokinetic parameters could be adequately predicted from a single trough concentration using a Bayesian approach.Conclusions: An absolute quantification method for nivolumab using LC-MS/MS was successfully developed and validated. Combined with PPK analysis, this method should be useful for the therapeutic drug monitoring of nivolumab in clinical practice.