Shu Pan, Zhao Ting, Wen Bo, Mendelsohn-Victor Kari, Sun Duxin, Friese Christopher R, Pai Manjunath P
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
School of Nursing, University of Michigan, Ann Arbor, MI, USA.
J Oncol Pharm Pract. 2020 Jun;26(4):794-802. doi: 10.1177/1078155219870591. Epub 2019 Sep 4.
Despite safe handling guidelines published by several groups, health care worker exposure to hazardous drugs continues to occur due to suboptimal engineering controls and low use of protective equipment. Simple, multi-target and specific analytical methods are needed so that acute exposures to these drugs in the workplace can be assessed rapidly. Our aim was to develop an analytical method for simultaneous detection and quantification of widely used cancer drugs to rule out accidental acute chemotherapy exposures in health care workers.
We examined the feasibility of alternate high-performance liquid chromatographic-tandem mass spectrometry methods to simultaneously detect eighteen chemotherapy analytes in plasma and urine. The linear concentration ranges tested during assay development were 0.1-50 ng/mL. After development of a multi-analyte assay protocol, plasma samples (n = 743) from a multi-center cluster-randomized clinical trial (n = 12 sites) of an hazardous drug educational intervention were assayed. Confirmatory assays were performed based on the individual acute-spill case-histories.
An innovative HPLC-multiple reaction monitoring-information dependent acquisition-enhanced production ion (MRM-IDA-EPI) analytical method was developed to simultaneously detect: cytarabine, gemcitabine, dacarbazine, methotrexate, topotecan, mitomycin, pemetrexed, irinotecan, doxorubicin, vincristine, vinblastine, ifosamide, cyclophosphamide, vinorelbine, bendamustine, etoposide, docetaxel, and paclitaxel. The retention times ranged from 4 min to 13 min for the analytical run. The limit of detection (MRM-IDA-EPI) and limit of quantitation (MRM) was 0.25 ng/mL and 0.1 ng/mL, respectively for most analytes. No detectable plasma concentrations were measured at baseline, post-intervention and in cases of documented acute spills. Use of a secondary tandem mass spectrometry approach was able to successfully rule out false positive results.
Development of a sensitive high-throughput multi-analyte cancer chemotherapy assay is feasible using an MRM-IDA-EPI method. This method can be used to rapidly rule out systemic exposure to accidental acute chemotherapy spills in health care workers.
尽管多个组织发布了安全操作指南，但由于工程控制欠佳以及防护设备使用率低，医护人员仍持续暴露于危险药物中。需要简单、多靶点且特异的分析方法，以便能快速评估工作场所中这些药物的急性暴露情况。我们的目的是开发一种分析方法，用于同时检测和定量广泛使用的癌症药物，以排除医护人员意外急性化疗暴露的情况。
我们研究了交替高效液相色谱 - 串联质谱法同时检测血浆和尿液中18种化疗分析物的可行性。在方法开发过程中测试的线性浓度范围为0.1 - 50 ng/mL。在制定了多分析物检测方案后，对一项危险药物教育干预的多中心整群随机临床试验（12个地点）中的743份血浆样本进行了检测。根据个体急性暴露事件病史进行确证检测。
开发了一种创新的高效液相色谱 - 多反应监测 - 信息依赖采集 - 增强产物离子（MRM - IDA - EPI）分析方法，可同时检测：阿糖胞苷、吉西他滨、达卡巴嗪、甲氨蝶呤、拓扑替康、丝裂霉素、培美曲塞、伊立替康、多柔比星、长春新碱、长春碱、异环磷酰胺、环磷酰胺、长春瑞滨、苯达莫司汀、依托泊苷、多西他赛和紫杉醇。分析运行的保留时间为4分钟至13分钟。大多数分析物的检测限（MRM - IDA - EPI）和定量限（MRM）分别为0.25 ng/mL和0.1 ng/mL。在基线、干预后以及有记录的急性暴露事件中均未检测到可测量的血浆浓度。使用二级串联质谱方法能够成功排除假阳性结果。
使用MRM - IDA - EPI方法开发灵敏的高通量多分析物癌症化疗检测方法是可行的。该方法可用于快速排除医护人员因意外急性化疗暴露而导致的全身暴露情况。
