den Brok Monique W J, Nuijen Bastiaan, Challa Eric E, Lutz Christian, Opitz Hans Georg, Beijnen Jos H
Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Anticancer Drugs. 2005 Aug;16(7):727-32. doi: 10.1097/01.cad.0000172833.70444.ba.
Imexon is an investigational anti-cancer agent, pharmaceutically formulated as a lyophilized solid for i.v. infusion requiring reconstitution and subsequent dilution in infusion fluid before infusion. Imexon contains a highly reactive aziridine ring in its structure, which limits its stability in aqueous solutions. In the present study, several in vitro studies were conducted to determine the administration parameters for use in the forthcoming phase I clinical trial. The stability of Imexon in the reconstituted solution and infusion solutions was investigated, including its tendency to degrade to its main degradation product BM41.209, and to its hydroxy and chloride adducts. The compatibility of the infusion solution with glass, low-density polyethylene and freeflex polyolefin containers, and its potency to cause vascular irritation and hemolysis upon i.v. infusion were investigated. Imexon was found to be stable for 8 h in the reconstituted product and for 2 h after dilution to infusion solution concentrations in normal saline. The infusion solution was compatible with the freeflex polyolefin container and polyvinylchloride infusion lining, showing no sorption of Imexon during a 15-min infusion duration and no release of the plasticizer diethylhexyl phthalate. Furthermore, Imexon infusion solution showed no indication for vascular irritation or hemolysis upon i.v. infusion, as measured with a static in vitro model with incubation with whole blood. In conclusion, Imexon should be administered using a freeflex polyolefin infusion container within 2 h after preparation and a 15-min infusion duration. The results obtained with an in vitro model show that no vascular irritation or hemolysis is expected upon i.v. infusion.
艾美克松是一种处于研究阶段的抗癌药物，其剂型为冻干固体，用于静脉输注，输注前需要复溶并随后在输液中稀释。艾美克松的结构中含有一个高反应性的氮丙啶环，这限制了它在水溶液中的稳定性。在本研究中，进行了多项体外研究以确定即将进行的I期临床试验的给药参数。研究了艾美克松在复溶溶液和输注溶液中的稳定性，包括其降解为主要降解产物BM41.209及其羟基和氯化物加合物的倾向。研究了输注溶液与玻璃、低密度聚乙烯和Freeflex聚烯烃容器的相容性，以及其静脉输注时引起血管刺激和溶血的可能性。发现艾美克松在复溶产物中稳定8小时，在稀释至生理盐水输注溶液浓度后稳定2小时。输注溶液与Freeflex聚烯烃容器和聚氯乙烯输液内衬相容，在15分钟的输注期间未显示艾美克松的吸附，也未释放增塑剂邻苯二甲酸二乙基己酯。此外，用全血孵育的静态体外模型测量，艾美克松输注溶液在静脉输注时未显示血管刺激或溶血迹象。总之，艾美克松应在制备后2小时内使用Freeflex聚烯烃输注容器给药，输注持续时间为15分钟。体外模型获得的结果表明，静脉输注时预计不会出现血管刺激或溶血。
