Johnston E, Crawford J, Blackwell S, Bjurstrom T, Lockbaum P, Roskos L, Yang B B, Gardner S, Miller-Messana M A, Shoemaker D, Garst J, Schwab G
Thoracic Oncology Program, Duke Comprehensive Cancer Center, Durham, NC 27710, USA.
J Clin Oncol. 2000 Jul;18(13):2522-8. doi: 10.1200/JCO.2000.18.13.2522.
To explore the use of SD/01 (a polyethylene glycol-conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia.
Thirteen patients with non-small-cell lung cancer were randomized to receive daily filgrastim (5 microg/kg/d) or a single injection of SD/01 (30, 100, or 300 microg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed.
Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 microg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 microg/kg. Dose-limiting toxicities were not noted. CD34(+) cells were mobilized in all cohorts.
A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34(+) cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.
探讨SD/01（一种聚乙二醇缀合的非格司亭，临床前研究显示其半衰期延长）在化疗引起的中性粒细胞减少症患者中的应用。
13例非小细胞肺癌患者被随机分为两组，一组在化疗前2周每日接受非格司亭（5微克/千克/天），另一组在化疗前2周单次注射SD/01（30、100或300微克/千克），并在给予卡铂和紫杉醇后24小时再次注射。进行了药效学、药代动力学和安全性分析。
SD/01的血清峰值浓度和血清浓度升高的持续时间取决于SD/01的剂量。化疗引起的中性粒细胞减少症患者中，SD/01浓度升高的持续时间更长。接受SD/01治疗的患者化疗前的中位绝对中性粒细胞计数（ANC）呈剂量依赖性增加，这种效应的持续时间也呈剂量依赖性。化疗后，非格司亭组和接受30微克/千克SD/01的组中位ANC最低点相似，接受100或300微克/千克SD/01的组最低点更高。未观察到剂量限制性毒性。所有组中CD34(+)细胞均被动员。
单次剂量的SD/01以剂量依赖性方式使SD/01血清浓度升高数天，且无明显毒性。SD/01对ANC和CD34(+)细胞动员的作用与每日使用非格司亭相当或更强。该分子的自我调节在与中性粒细胞减少相关的各种临床环境中提供了潜在的治疗优势。
