Kehrer Diederik F S, Bos Annelies M, Verweij Jaap, Groen Harry J, Loos Walter J, Sparreboom Alex, de Jonge Maja J A, Hamilton Marta, Cameron Terri, de Vries Elisabeth G E
Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek and University Hospital, Rotterdam, The Netherlands.
J Clin Oncol. 2002 Mar 1;20(5):1222-31. doi: 10.1200/JCO.2002.20.5.1222.
To determine the maximum-tolerated and recommended dose, toxicity profile, and pharmacokinetics of the liposomal topoisomerase I inhibitor lurtotecan (NX 211) administered as a 30-minute intravenous infusion once every 3 weeks in cancer patients.
NX 211 was administered by peripheral infusion. Dose escalation decisions were based on all toxicities during the first cycle as well as pharmacokinetic parameters. Serial plasma, whole blood, and urine samples were collected for up to 96 hours after the end of infusion, and drug levels were determined by high-performance liquid chromatography.
Twenty-nine patients (16 women; median age, 56 years; range, 39 to 74 years) received 77 courses of NX 211 at dose levels of 0.4 (n = 3), 0.8 (n = 6), 1.6 (n = 3), 3.2 (n = 6), 3.8 (n = 6), and 4.3 mg/m(2) (n = 5). Neutropenia and thrombocytopenia were the dose-limiting toxicities and were not cumulative. Other toxicities were mild to moderate. Nine patients had stable disease while undergoing treatment. The systemic clearance of lurtotecan in plasma and whole blood was 0.82 +/- 0.78 L/h/m(2) and 1.15 +/- 0.96 L/h/m(2), respectively. Urinary recovery (Fu) of lurtotecan was 10.1% +/- 4.05% (range, 4.9% to 18.9%). In contrast to systemic exposure measures, the dose excreted in urine (ie, dose x Fu) was significantly related to the percent decrease in neutrophil and platelet counts at nadir (P <.00001).
The dose-limiting toxicities of NX 211 are neutropenia and thrombocytopenia. The recommended dose for phase II studies is 3.8 mg/m(2) once every 3 weeks. Pharmacologic data suggest a relationship between exposure to lurtotecan and NX 211-induced clinical effects.
确定脂质体拓扑异构酶I抑制剂鲁替康（NX 211）在癌症患者中每3周进行一次30分钟静脉输注时的最大耐受剂量和推荐剂量、毒性特征及药代动力学。
通过外周输注给予NX 211。剂量递增决策基于第一个周期内的所有毒性以及药代动力学参数。在输注结束后长达96小时内采集系列血浆、全血和尿液样本，通过高效液相色谱法测定药物水平。
29例患者（16例女性；中位年龄56岁；范围39至74岁）接受了77个疗程的NX 211，剂量水平分别为0.4（n = 3）、0.8（n = 6）、1.6（n = 3）、3.2（n = 6）、3.8（n = 6）和4.3 mg/m²（n = 5）。中性粒细胞减少和血小板减少是剂量限制性毒性，且无累积性。其他毒性为轻度至中度。9例患者在接受治疗期间病情稳定。鲁替康在血浆和全血中的全身清除率分别为0.82±0.78 L/h/m²和1.15±0.96 L/h/m²。鲁替康的尿回收率（Fu）为10.1%±4.05%（范围4.9%至18.9%）。与全身暴露指标相反，尿中排泄的剂量（即剂量×Fu）与最低点时中性粒细胞和血小板计数的下降百分比显著相关（P <.00001）。
NX 211的剂量限制性毒性为中性粒细胞减少和血小板减少。II期研究的推荐剂量为每3周一次3.8 mg/m²。药理学数据表明鲁替康暴露与NX 211诱导的临床效应之间存在关联。
