目的 研究聚乙二醇化重組人粒細(xì)胞集落刺激因子（PEG-G-CSF）注射液在健康人體單次給藥的藥動(dòng)學(xué)（PK）和藥效學(xué)（PD）特征，評(píng)價(jià)其PK/PD相關(guān)性。方法 采用單中心、隨機(jī)、雙盲、安慰劑對(duì)照試驗(yàn)設(shè)計(jì)，36例健康受試者分別單次sc PEG-G-CSF注射液30、60、100、200 μg/kg，分別于給藥前（0 h），給藥后1、3、6、8、10、12、24、48、72、96、120、144、192、240、312、408 h采肘靜脈血，雙抗體夾心酶聯(lián)免疫分析（ELISA）法檢測(cè)血清藥物濃度，所有血藥濃度-時(shí)間數(shù)據(jù)采用DAS3.2.4藥動(dòng)學(xué)程序軟件進(jìn)行處理，用非房室模型擬合計(jì)算藥動(dòng)學(xué)參數(shù)，t_max、C_max采用實(shí)測(cè)值；AUC采用梯形法計(jì)算。并同步監(jiān)測(cè)血清絕對(duì)中性粒細(xì)胞計(jì)數(shù)（ANC）。結(jié)果 在30~100 μg/kg劑量范圍內(nèi)t_max較為恒定，為8.0~12.4 h；當(dāng)給藥劑量升至200 μg/kg時(shí)，t_max后移至24.0 h；C_max和AUC_{0~408 h}隨劑量遞增而呈更大比例增大，即當(dāng)劑量增加約7倍時(shí)，C_max和AUC_{0~408 h}分別增大14、26倍。各劑量組t_1/2Z較為一致（約61 h）。血清中的ANC水平與給藥前比較均有顯著升高，ANC的達(dá)峰時(shí)間（t_max（ANC））隨著劑量增加而延長(zhǎng)，且明顯滯后于血藥濃度的t_max；ANC的峰濃度（C_max（ANC））和隨時(shí)間變化曲線下面積（AUC_{0~408h（ANC）}）與給藥劑量的相關(guān)性不甚明顯。給藥后1周內(nèi)血液中ANC一直維持在較高水平范圍內(nèi)，而血清中PEG-G-CSF的濃度在8~24 h達(dá)到峰值，較PD的達(dá)峰時(shí)間早。結(jié)論 健康受試者單次sc PEG-G-CSF注射液30~200 μg/kg呈現(xiàn)非線性動(dòng)力學(xué)特征。在血液中的清除主要經(jīng)嗜中性粒細(xì)胞受體介導(dǎo)，并且具有自我調(diào)節(jié)的清除機(jī)制。與非PEG化的rhG-CSF比較，PEG-G-CSF顯示了其在體內(nèi)的長(zhǎng)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.

國(guó)家重大新藥創(chuàng)制科技重大專項(xiàng)（2012ZX09304002）