Fetterly Gerald J, Grasela Thaddeus H, Sherman Jeffrey W, Dul Jeanne L, Grahn Amy, Lecomte Diane, Fiedler-Kelly Jill, Damjanov Nevena, Fishman Mayer, Kane Michael P, Rubin Eric H, Tan Antoinette R
Cognigen Corporation, Buffalo, NY 14263, USA.
Clin Cancer Res. 2008 Sep 15;14(18):5856-63. doi: 10.1158/1078-0432.CCR-08-1046.
To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients.
LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m(2)). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection.
The MTD of LEP-ETU was identified as 325 mg/m(2). DLTs occurring at 375 mg/m(2) consisted of febrile neutropenia and neuropathy. The C(max) and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 mug/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m(2) q3w. For a dose of 110 mg/m(2) given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w.
LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m(2) LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m(2) Taxol q3w. A 275 mg/m(2) dose may offer an improved therapeutic index.
评估脂质体包裹紫杉醇易使用剂型（LEP - ETU）的最大耐受剂量（MTD）、剂量限制性毒性（DLT）和药代动力学，并确定癌症患者中LEP - ETU浓度与中性粒细胞减少时间进程之间的关系。
对88例患者给予LEP - ETU，其中63例患者在每3周（q3w）进行1.5小时和3小时输注后可进行药代动力学/药效学（PK/PD）分析（剂量范围为135 - 375 mg/m²）。使用3 + 3上下剂量递增算法确定MTD。进行PK/PD建模以描述紫杉醇浓度与中性粒细胞计数之间的时间关系。模拟评估剂量和给药方案对中性粒细胞减少严重程度的影响，以帮助指导剂量选择。
LEP - ETU的MTD确定为325 mg/m²。375 mg/m²时出现的DLT包括发热性中性粒细胞减少和神经病变。LEP - ETU的Cmax和血浆浓度 - 时间曲线下面积与剂量增加不成正比。PK/PD模型显示，每10μg/mL总紫杉醇浓度下，LEP - ETU对中性粒细胞增殖的抑制率为9.1%。在275至325 mg/m² q3w的剂量范围内，4级中性粒细胞减少的发生率从33%增加到42%。对于每周给予110 mg/m²的剂量，估计4级中性粒细胞减少发生率为16%，而相同总剂量q3w给药时为42%。
LEP - ETU可以比紫杉醇更高的剂量安全给药。建模和模拟研究预测，相对于175 mg/m²紫杉醇q3w观察到的情况，325 mg/m² LEP - ETU q3w提供了可接受的中性粒细胞减少事件。275 mg/m²的剂量可能提供更好的治疗指数。
