Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors
Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors
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DOI：
10.1038/aps.2012.44
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发表时间：
2012-06-01
影响因子：
8.2
通讯作者：
Cheng, Guang
中科院分区：
文献类型：
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作者：
Yan, Zhao;Zhu, Zhong-ling;Cheng, Guang
目的：方法：在单剂量药代动力学研究中，16例晚期实体瘤患者分别静脉滴注硫酸长春新碱脂质体（VSLI）1.5、2.0或2.3 mg.m（-2）。另6例接受硫酸长春新碱（VCR，2.0 mg）治疗的患者作为对照。在多次给药药代动力学研究中，12例患者接受VSLI（1.5或1.8 mg.m（-2））静脉输注，每周一次，连续4周。采用液相色谱-串联质谱法（LC-MS/MS）测定VSLI的血药浓度。结果：单次静脉输注VSLI后，血浆浓度呈双指数下降曲线。3个剂量组的主要药代动力学参数之间未观察到统计学显著性差异。与接受VCR治疗的患者相比，接受VSLI治疗的患者显示血药浓度-时间曲线下面积（AUC）增加，血浆清除率降低。在多次给药研究的第4个周期，每周给药前所有受试者的VCR血药浓度均低于定量下限（LLOQ）。多次给药和单次给药（1.5 mg.m（-2））组受试者计算的药代动力学参数无显著差异。虽然脂质体VCR给药可显著升高VCR的血浆浓度，但VSLI相关不良事件与常规VCR相关不良事件相似。结论：VSLI与常规VCR相比，清除率较低，AUC较高。在连续4周暴露于VSLI的患者中未观察到蓄积。VSLI在受试者中通常耐受。对于晚期实体瘤患者的治疗，VSLI的II期剂量可推荐为4剂1.5 mg.m（-2）。
Aim: To evaluate the single- and multiple-dose pharmacokinetics of vincristine sulfate liposomes (VSLI) in patients with advanced solid tumors.Methods: In single-dose pharmacokinetic study, 16 patients were administered VSLI (1.5, 2.0, or 2.3 mg.m(-2)) through intravenous infusion. Another 6 patients receiving vincristine sulfate (VCR, 2.0 mg) were taken as the control. In multiple-dose pharmacokinetic study, 12 patients were administered VSLI (1.5 or 1.8 mg.m(-2)) through intravenous infusion weekly for 4 consecutive weeks. The plasma concentration of VSLI was determined using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.Results: After intravenous infusion of the single dose of VSLI, the plasma concentrations were characterized by bi-exponential decline curves. No statistically significant differences were observed between the main pharmacokinetic parameters in the 3 dose groups. Compared with the patients receiving VCR, the patients treated with VSLI displayed an increase in the area under the plasma concentration vs time curve (AUC), and a decrease in plasma clearance rates. On the 4th cycle in the multiple-dose study, the plasma concentration of VCR in all subjects prior to the weekly administration was below the lower limit of quantification (LLOQ). The calculated pharmacokinetic parameters from the subjects in the multiple- and single-dose (1.5 mg.m(-2)) groups had no significant differences. Although the administration of liposomal VCR may significantly elevate the plasma concentration of VCR, VSLI-associated adverse events were similar to those associated with conventional VCR.Conclusion: VSLI exhibits a lower clearance and a higher AUC compared with conventional VCR. No accumulation was observed in patients exposed to VSLI for 4 consecutive weeks. VSLI was generally tolerated in the subjects. The phase II dose of VSLI may be recommended as 4 doses of 1.5 mg.m(-2) for treatment of patients with advanced solid tumors.