McEwan Pauline E, Bailey Lynn, Trost David, Scull Christopher, Keating John H, Williams Misty, Guttendorf Robert J
Biologics Consulting, Alexandria, VA, USA.
CBSET Inc, Lexington, MA, USA.
Int J Toxicol. 2018 Nov/Dec;37(6):434-447. doi: 10.1177/1091581818811306. Epub 2018 Nov 19.
Regional therapies for metastatic liver disease have garnered interest in recent years due to technological advances in drug delivery. A percutaneous hepatic perfusion (PHP) using a newly developed generation 2 (GEN2) filtration system was designed to mitigate systemic toxicity and cardiovascular risk associated with hepatic blood filtration during hepatic artery infusion of the chemotherapy drug melphalan. The GEN2 system was evaluated in healthy swine, and plasma samples were assessed for clinical chemistry, melphalan toxicokinetics (TK), inflammatory cytokines, catecholamines, hematological, and cardiac biomarkers. Cardiovascular safety was assessed by echocardiography, electrocardiogram, and telemetry. Toxicology parameters included clinical signs, body weight, gross pathology, and histopathology. There were no treatment-related deaths associated with the PHP procedure with GEN2 filtration, and all animals survived to scheduled necropsy. Assessment of the pharmacokinetic/TK plasma concentrations of melphalan demonstrated that the GEN2 filter was able to extract melphalan from blood with high efficiency and reduce melphalan exposure in the systemic circulation. The hemodynamic, immunosuppressive, immunotoxic, cardiotoxic, and histopathologic effects of melphalan were limited. The significant hemodynamic challenge imposed by filtration resulted in a compensatory tachycardia with supranormal left ventricular function, although no wall motion abnormalities were detected and left ventricular function remained normal. Catecholamines decreased and then quickly rebounded during washout. Transient and reversible effects of treatment on cardiac enzymes, catecholamines, and cytokines and reversible hemodynamic effects without cardiac damage indicated that PHP with melphalan was not cardiotoxic or immunotoxic under the conditions tested, due to high efficiency of the filtration system limiting exposure of melphalan to the systemic circulation.
近年来，由于药物递送技术的进步，转移性肝病的区域治疗引起了人们的关注。使用新开发的第二代（GEN2）过滤系统的经皮肝灌注（PHP）旨在减轻在肝动脉输注化疗药物美法仑期间与肝血滤过相关的全身毒性和心血管风险。在健康猪中对GEN2系统进行了评估，并对血浆样本进行了临床化学、美法仑毒代动力学（TK）、炎性细胞因子、儿茶酚胺、血液学和心脏生物标志物的评估。通过超声心动图、心电图和遥测评估心血管安全性。毒理学参数包括临床体征、体重、大体病理学和组织病理学。与使用GEN2过滤的PHP程序相关的没有治疗相关死亡，所有动物均存活至预定的尸检。对美法仑的药代动力学/TK血浆浓度的评估表明，GEN2过滤器能够高效地从血液中提取美法仑并减少全身循环中美法仑的暴露。美法仑的血流动力学、免疫抑制、免疫毒性、心脏毒性和组织病理学影响有限。尽管未检测到壁运动异常且左心室功能保持正常，但过滤带来的显著血流动力学挑战导致代偿性心动过速，左心室功能超常。儿茶酚胺在冲洗过程中先降低然后迅速反弹。治疗对心脏酶、儿茶酚胺和细胞因子的短暂且可逆的影响以及无心脏损伤的可逆血流动力学影响表明，在所测试的条件下，美法仑PHP不是心脏毒性或免疫毒性的，这是由于过滤系统的高效率限制了美法仑在全身循环中的暴露。
