Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
Ann Surg Oncol. 2010 Sep;17(9):2510-7. doi: 10.1245/s10434-010-1028-x. Epub 2010 Mar 26.
Peritoneal carcinomatosis (PC) remains a dreaded clinical syndrome and a common evolution of gastrointestinal and ovarian cancers. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has emerged as a promising strategy in the management of PC. In this study, a novel paclitaxel (Pac) formulation was investigated for its toxicity and bioavailability during HIPEC compared with Taxol.
The maximum tolerated dose (MTD) after HIPEC of both formulations (Taxol and Pac/RAME-beta-CD) was determined. MTD was defined as the highest nonlethal dose with a reduction in body weight of < or = 10% over 2 weeks. Blood parameters (red blood cell and white blood cell count, creatinine, ALT, and GGT) were evaluated over 20 days. Bioavailability of both Pac formulations after HIPEC was determined under normothermic (37 degrees C) and hyperthermic (41 degrees C) conditions for 90 min.
Following HIPEC, both formulations had a similar MTD: 0.24 mg paclitaxel per ml. Red blood cell count decreased to a minimum after 10 days and was not fully recovered after 20 days for both formulations. White blood cell monitoring showed a significant increase in neutrocytes at day 10 and 15 for the Pac/RAME-beta-CD formulation. Liver and kidney parameters did not change significantly. Bioavailability data of Pac/RAME-beta-CD showed a 40-fold increase of the area under the curve (AUC) of plasma concentrations compared with Taxol. Hyperthermia yielded no significant differences in bioavailability data.
These results showed that both formulations had a similar toxicity profile but differed significantly in bioavailability.
腹膜癌病（PC）仍然是一种可怕的临床综合征，也是胃肠道癌和卵巢癌的常见进展。近年来，细胞减灭术后腹腔内热化疗（HIPEC）已成为 PC 治疗的一种很有前途的策略。在这项研究中，与 Taxol 相比，研究了一种新型紫杉醇（Pac）制剂在 HIPEC 中的毒性和生物利用度。
确定了两种制剂（Taxol 和 Pac/RAME-β-CD）在 HIPEC 后的最大耐受剂量（MTD）。MTD 定义为体重在 2 周内减轻<或=10%的最高非致死剂量。在 20 天内评估血液参数（红细胞和白细胞计数、肌酐、ALT 和 GGT）。在 90 分钟内，在常温（37°C）和高温（41°C）条件下，测定两种 Pac 制剂在 HIPEC 后的生物利用度。
两种制剂在 HIPEC 后具有相似的 MTD：每毫升 0.24 毫克紫杉醇。两种制剂的红细胞计数在 10 天后降至最低，20 天后未完全恢复。白细胞监测显示，Pac/RAME-β-CD 制剂在第 10 天和第 15 天中性粒细胞显著增加。肝肾功能参数无明显变化。Pac/RAME-β-CD 的生物利用度数据显示，与 Taxol 相比，血浆浓度的曲线下面积（AUC）增加了 40 倍。高温对生物利用度数据没有显著影响。
这些结果表明，两种制剂具有相似的毒性谱，但生物利用度有显著差异。
