目的 研究聚乙二醇化重组人粒细胞集落刺激因子（PEG-G-CSF）注射液在健康人体单次给药的药动学（PK）和药效学（PD）特征，评价其PK/PD相关性。方法 采用单中心、随机、双盲、安慰剂对照试验设计，36例健康受试者分别单次sc PEG-G-CSF注射液30、60、100、200 μg/kg，分别于给药前（0 h），给药后1、3、6、8、10、12、24、48、72、96、120、144、192、240、312、408 h采肘静脉血，双抗体夹心酶联免疫分析（ELISA）法检测血清药物浓度，所有血药浓度-时间数据采用DAS3.2.4药动学程序软件进行处理，用非房室模型拟合计算药动学参数，t_max、C_max采用实测值；AUC采用梯形法计算。并同步监测血清绝对中性粒细胞计数（ANC）。结果 在30~100 μg/kg剂量范围内t_max较为恒定，为8.0~12.4 h；当给药剂量升至200 μg/kg时，t_max后移至24.0 h；C_max和AUC_{0~408 h}随剂量递增而呈更大比例增大，即当剂量增加约7倍时，C_max和AUC_{0~408 h}分别增大14、26倍。各剂量组t_1/2Z较为一致（约61 h）。血清中的ANC水平与给药前比较均有显著升高，ANC的达峰时间（t_max（ANC））随着剂量增加而延长，且明显滞后于血药浓度的t_max；ANC的峰浓度（C_max（ANC））和随时间变化曲线下面积（AUC_{0~408h（ANC）}）与给药剂量的相关性不甚明显。给药后1周内血液中ANC一直维持在较高水平范围内，而血清中PEG-G-CSF的浓度在8~24 h达到峰值，较PD的达峰时间早。结论 健康受试者单次sc PEG-G-CSF注射液30~200 μg/kg呈现非线性动力学特征。在血液中的清除主要经嗜中性粒细胞受体介导，并且具有自我调节的清除机制。与非PEG化的rhG-CSF比较，PEG-G-CSF显示了其在体内的长效特性。

Objective To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of Pegylated Recombinant Human Granulocyte Colony Stimulating Factor (PEG-G-CSF) Injection after a single dose administration in healthy volunteers, and study the relationship between PK and PD. Methods A single center, randomized, double-blind, placebo-controlled test was used, and 36 healthy volunteers were sc administered at single doses of 30, 60, 100, and 200 μg/kg PEG-G-CSF Injection. The cubital vein blood was collected at 0, 1, 3, 6, 10, 8, 12, 24, 48, 72, 96, 120, 144, 192, 240, 312, and 408 h, respectively. A sandwich enzyme-linked immunosorbent assay (ELISA) method was developed to determine the dynamic changes of serum drug concentration. All serum concentration time data were processed by DAS3.2.4 pharmacokinetic program. The pharmacokinetic parameters were calculated by non compartmental model fitting. The measured values of t_max and C_max were used, and AUC was calculated by trapezoid method. The changes of absolute neutrophil count (ANC) in serum were monitored synchronously. Results In the dose range of 30-100 μg/kg, t_max was constant between 8.0 and 12.4 h. When the dosage was increased to 200 μg/kg, and t_max was delayed to 24.0 h. With increasing doses of a greater proportion, C_max and AUC_{0~408 h} were increased in a greater than dose proportional manner. When the dose increased to about 7 times, C_max and AUC_{0~408 h} were increased 14 and 26 times, respectively. T_1/2Z in each dose group was more consistent (about 61 h). The serum ANC levels were significantly increased after treatment. The peak time of t_max(ANC) prolonged with the increase of dosage, and obviously lagged behind the blood concentration of t_max. The peak concentration of C_max(ANC) and the curves of AUC_0~408h(ANC) were not very obviously related to dosage. Within 1 week after administration, blood ANC remained at a high level, while serum PEG-G-CSF concentrations reached peak concentration at 8-24 h, earlier than PD peak time. Conclusion PEG-G-CSF exhibits nonlinear pharmacokinetics at single dose of 30-200 μg/kg in healthy subjects with single sc PEG-G-CSF Injection. Drug clearance in the serum is mainly mediated by neutrophil receptors and has a self regulating clearance mechanism. Compared with rhG-CSF, PEG-G-CSF fully displays its characteristics of long-lasting properties in vivo.

国家重大新药创制科技重大专项（2012ZX09304002）