Drug Delivery Division, Biocompatibles UK Ltd, Farnham Business Park, Weydon Lane, Farnham, Surrey, UK.
J Mater Sci Mater Med. 2013 Jan;24(1):115-27. doi: 10.1007/s10856-012-4768-2. Epub 2012 Sep 27.
Irinotecan eluting embolization beads (DEBIRI) are currently being evaluated in the clinic for the treatment of colorectal cancer metastases to the liver. The aim of this study was to determine the safety and pharmacokinetics associated with two cycles of hepatic embolization using DEBIRI followed by intravenous administration of irinotecan. Pigs were embolized with DEBIRI (100-300 μm, 100 mg dose, n = 6) and blood samples taken over 24 h to determine plasma levels of irinotecan and SN-38 metabolite and for haematology and biochemistry. At 24 h an IV infusion of 250 mg/m(2) of irinotecan was administered and the plasma levels taken again. This cycle was repeated 3 weeks later. A single animal was subjected to a more aggressive regimen of embolization with 200 mg bead dose and IV of 350 mg/m(2) for two cycles. Three animals were sacrificed at 6 weeks and the remaining four (n = 3 standard dose, n = 1 high dose) animals at 12 weeks and detailed histopathology performed. All animals tolerated the treatments well, with only minor changes in haematological and biochemical parameters. There was no overlap in drug plasma levels observed from the bead and IV treatments when given 24 h apart and no difference between the pharmacokinetic profiles of the two cycles separated by 3 weeks. Irinotecan plasma AUC values were similar in both the embolization and IV arms of the study. C(max) values obtained during the IV arms of the study are approximately double that of the embolization arms whilst T(max) times are shorter in the IV arms, supporting extended release of drug from the beads. Bioavailability for bead-based delivery was double that for IV administration, which was attributed to reduced clearance of the drug when delivered by this route. No additive toxicity was observed as a consequence of the combined treatments. The combination of irinotecan delivery via drug eluting bead and IV was well-tolerated with no significant clinical effects. Pharmacokinetic analyses suggest the bioavailability from bead-based delivery of drug is double that of IV infusion, attributable to reduced drug clearance for the former.
伊立替康洗脱微球（DEBIRI）目前正在临床中评估用于治疗结直肠癌肝转移。本研究的目的是确定使用 DEBIRI 进行两次肝栓塞后静脉注射伊立替康相关的安全性和药代动力学。猪接受 DEBIRI（100-300μm，100mg 剂量，n=6）栓塞，在 24 小时内采集血液样本以确定伊立替康和 SN-38 代谢物的血浆水平，并进行血液学和生化学检查。在 24 小时时，给予 250mg/m²的伊立替康静脉滴注，并再次采集血浆水平。3 周后重复该周期。一只动物接受了更具侵袭性的栓塞方案，给予 200mg 珠剂量和 350mg/m²的 IV 剂量，进行两个周期。6 周时处死 3 只动物，12 周时处死其余 4 只（n=3 标准剂量，n=1 高剂量）动物，并进行详细的组织病理学检查。所有动物均耐受治疗，仅血液学和生化参数有轻微变化。当 24 小时间隔给予珠和 IV 治疗时，观察到药物血浆水平没有重叠，并且 3 周间隔的两个周期的药代动力学曲线没有差异。伊立替康的 AUC 值在栓塞和 IV 研究臂中相似。研究中 IV 臂获得的 C(max)值大约是栓塞臂的两倍，而 IV 臂的 T(max)时间更短，支持药物从珠中延长释放。基于珠的递送的生物利用度是 IV 给药的两倍，这归因于通过该途径给药时药物清除率降低。由于联合治疗，未观察到附加毒性。伊立替康通过药物洗脱珠和 IV 联合给药的组合耐受良好，无明显临床影响。药代动力学分析表明，基于珠的药物递送的生物利用度是 IV 输注的两倍，这归因于前者的药物清除率降低。
