目的研究癌症患者化疗后单次sc不同剂量的注射用聚乙二醇化重组人粒细胞集落刺激因子(PEG-rhG-CSF)的药动学。方法采用酶联免疫分析检测(ELISA)法测定癌症患者sc PEG-rhG-CSF后的血药浓度,实验数据用3P97药动程序拟合分析并计算药动学参数。结果癌症患者化疗后48 h单次sc PEG-rhG-CSF 30、60、100、200μg/kg,每组4例病人的平均消除半衰期(t1/2ke)差异不大,分别为(47.8±7.3)、(49.8±6.9)、(45.7±9.6)和(44.6±6.3)h;平均达峰时间(tmax)分别为(21.0±6.0)、(24.0±0)、(21.0±6.0)、(42.0±12.0)h;平均清除率(CL)分别为(5.44±0.86)、(5.06±0.69)、(3.36±0.35)、(3.31±1.20)mL/(kg.h),CL有随剂量增加而下降的趋势;平均达峰浓度(Cmax)分别为(54.0±10.8)、(129.0±20.9)(、344.9±73.4)、(828.9±245.6)ng/mL;平均药时曲线下面积(AUC0~432 h)分别为(5 714±786)(、12 781±1 745)(、32 714±6 486)(、85 142±26 186)h.ng/mL;Cmax和AUC与剂量均呈正相关。结论PEG-rhG-CSF的较长半衰期和较慢清除率(与rhG-CSF相比)保证了该药在体内的长效特性。

Objective To explore clinical pharmacokinetics by sc injection of pegylated recombinant human granulocyte colony-stimulating factor(PEG-rhG-CSF) at various doses to cancer patients with chemotherapy-induced neutropenia.Methods Serum concentration of PEG-rhG-CSF was measured by an enzyme-linked immunosorbent assay(ELISA).Pharmacokinetic parameters were calculated with 3P97 software.Results After 48 h chemotherapeutic treatment,patients received single sc doses of PEG-rhG-CSF at 30,60,100,and 200 μg/kg.In every group with four cases showed no significant difference,the mean elimination half-life(t1/2ke) was(47.8±7.3),(49.8±6.9),(45.7±9.6),and(44.6±6.3) h,respectively.The mean time to reach peak concentration(tmax) was(21.0±6.0),(24.0±0),(21.0±6.0),and(42.0±12.0) h.The mean drug clearance from serum(CL) was(5.44±0.86),(5.06±0.69),(3.36±0.35),and(3.31±1.20) mL/(h·kg).The mean peak concentration(Cmax) was(54.0±10.8),(129.0±20.9),(344.9±73.4),and(828.9±245.6) ng/mL. The mean area under the serum concentration-time curve(AUC0～432 h) was(5 714±786),(12 781±1 745),(32 714±6 486),and(85 142±26 186) h·ng/mL.Pharmacokinetics of PEG30-rhG-CSF was dose-dependent,both Cmax and the AUC were increased with the increasing doses.CL,however,was decreased with dose increasing.Conclusion Due to the longer t1/2ke and slower CL,PEG-rhG-CSF results in more desirable pharmacokinetic properties in vivo compared to rhG-CSF.

国家“863计划”资助项目(2003AA2Z347D);国家“973计划”资助项目(2004CB518902)