Gelderblom Hans, Salazar Ramon, Verweij Jaap, Pentheroudakis George, de Jonge Maja J A, Devlin Martin, van Hooije Christel, Seguy Francis, Obach Rosendo, Pruñonosa Joan, Principe Paola, Twelves Chris
Department of Medical Oncology, Erasmus MC-Daniel den Hoed, 3008 AE Rotterdam, the Netherlands.
Clin Cancer Res. 2003 Sep 15;9(11):4101-7.
Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics.
An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured.
Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low.
The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability.
地氟莫特坎（BN80915）是一种E环修饰的喜树碱类似物，与其他拓扑异构酶I抑制剂相比，其在血浆中具有更高的内酯稳定性，这是其抗肿瘤活性的一个潜在优势。与其他喜树碱类药物一样，口服给药具有药理学和临床优势。本I期研究旨在评估口服地氟莫特坎给药的可行性，确定最大耐受剂量、其生物利用度，并探索其药代动力学。
首先静脉推注给药以评估地氟莫特坎的生物利用度。14天后，对患有实体恶性肿瘤的成年患者口服地氟莫特坎，每日一次，共5天，每3周重复一次。检测BN80915及其开环内酯形式BN80942。
22名患者进入研究，共接受了57个周期的口服地氟莫特坎治疗，固定剂量水平分别为0.10、0.20、0.27和0.35mg。主要毒性为血液学毒性，但部分患者出现脱发、轻度胃肠道毒性和疲劳。在0.35mg剂量水平，4名患者中有2名出现剂量限制性毒性，1名患者出现3级血小板减少伴鼻出血和发热性中性粒细胞减少，另1名患者出现无并发症的4级中性粒细胞减少持续超过7天。在0.27mg剂量水平毒性可接受，12名患者中有3名出现剂量限制性毒性（4级中性粒细胞减少>7天，1名患者并发发热但无其他感染迹象）。接受两个周期的地氟莫特坎治疗后，6名患者病情稳定，其中2名患者分别维持了9个月和超过1年。在所研究的剂量范围内，地氟莫特坎的药代动力学呈线性。全身暴露与白细胞计数下降相关。所有剂量水平的平均口服生物利用度（±标准差）为72.24±59.2%。BN80915的尿排泄量非常低。
II期研究推荐的口服地氟莫特坎剂量为每3周0.27mg/天×5天。该方案方便且耐受性一般良好，具有良好的药代动力学特征和高但可变的生物利用度。
