Graham Janet S, Falk Stephen, Samuel Leslie M, Cendros Josep M, Evans T R Jeffry
The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 OYN, UK.
Cancer Chemother Pharmacol. 2009 Apr;63(5):945-52. doi: 10.1007/s00280-008-0795-6. Epub 2008 Jul 25.
Diflomotecan, a homocamptothecin, targets DNA topoisomerase I. Previous clinical trials have demonstrated a variable degree of dose limiting toxicity. The purpose of this study was to further evaluate the safety and pharmacokinetic profile of a range of diflomotecan doses administered intravenously.
Patients with advanced solid malignant tumours, refractory to standard therapies, with adequate haematologic, renal and hepatic function, received diflomotecan administered as a 20 min intravenous infusion every 21 days. Cohorts of six patients were recruited sequentially to one of three fixed starting dose groups-2, 4, or 7 mg, with drug administered by fixed-dose rather than dosing by body surface area. Pharmacokinetic analyses were performed on serial blood samples taken over the first 24 h after diflomotecan administration (cycles 1 and 2). Cytochrome P450 3A4 (CYP3A4) activity was determined by an erythromycin breath test (EBT) prior to diflomotecan administration in cycles 1 and 2.
Thirteen patients, were treated with a starting dose of either 2 mg (n = 8) or 4 mg (n = 5) of diflomotecan. Dose limiting toxicities (DLTs) were observed in 1 patient in the 2 mg starting dose level (grade 4 neutropenia which lasted for 8 days), and in 2 of 5 patients enrolled at the 4 mg starting dose level (grade 4 neutropenia for 11 days; grade 4 neutropenia leading to withdrawal from the study), and no further dose escalation was performed. Pharmacokinetic analyses revealed a less than dose-proportional increase in diflomotecan and for the two metabolites BN80942 and P-20, with a magnitude of P-20 exposure similar to the parent drug. There was a high inter-patient variability in diflomotecan exposure similar to that observed with other camptothecin derivatives. One minor response was observed in a patient with oesophageal cancer.
Diflomotecan administered as a 20-min intravenous infusion 3-weekly is characterised by a variable pharmacokinetic profile. Alternative oral dosing schedules of diflomotecan have been shown to display a more predictable PK/PD and safety profile and should be selected for further evaluation in Phase II clinical trials.
地氟莫特坎是一种喜树碱类似物，作用于DNA拓扑异构酶I。先前的临床试验已证明其剂量限制性毒性程度各异。本研究的目的是进一步评估静脉注射一系列地氟莫特坎剂量的安全性和药代动力学特征。
患有晚期实体恶性肿瘤、对标准疗法耐药、血液学、肾脏和肝脏功能良好的患者，每21天接受一次20分钟静脉输注的地氟莫特坎治疗。将六名患者组成的队列依次纳入三个固定起始剂量组之一——2、4或7毫克，药物按固定剂量给药，而非按体表面积给药。在给予地氟莫特坎后的头24小时（第1和第2周期）采集系列血样进行药代动力学分析。在第1和第2周期给予地氟莫特坎之前，通过红霉素呼气试验（EBT）测定细胞色素P450 3A4（CYP3A4）活性。
13名患者接受了起始剂量为2毫克（n = 8）或4毫克（n = 5）的地氟莫特坎治疗。在2毫克起始剂量水平的1名患者中观察到剂量限制性毒性（4级中性粒细胞减少持续8天），在4毫克起始剂量水平入组的5名患者中有2名出现剂量限制性毒性（4级中性粒细胞减少11天；4级中性粒细胞减少导致退出研究），因此未进一步提高剂量。药代动力学分析显示，地氟莫特坎及其两种代谢物BN80942和P - 20的增加与剂量不成比例，P - 20的暴露量与母体药物相似。地氟莫特坎的暴露在患者间存在高度变异性，与其他喜树碱衍生物观察到的情况类似。在一名食管癌患者中观察到一次轻微缓解。
每3周进行一次20分钟静脉输注的地氟莫特坎，其药代动力学特征各异。已证明地氟莫特坎的替代口服给药方案显示出更可预测的药代动力学/药效学和安全性特征，应选择用于II期临床试验的进一步评估。
