Y型聚乙二醇重组人粒细胞集落刺激因子注射液Ⅰ期临床药代动力学和药效学研究

摘要

Objective: To evaluate the pharmacokinetic and pharmacodynamic of Y-pegylated recombinant human granulocyte-colony stimulating factor (YPEG-rHuG-CSF) in the prophylaxis of chemotherapy-induced neu-tropenia. Methods: 30 patients received three cycles of the same chemotherapy regimen. In cycle 1 , patients just were treated with chemotherapy. In cycle 2, patients would receive a single subcutaneous injection of YPEG-rHuG-CSF 48 hours after chemotherapy, dose levels of 10 (preliminary experiment) , 20, 30, 45 or 60 μg·kg-1. In cycle 3 , patients patients would receive a single subcutaneous injection of G-CSF 48 hours after chemotherapy until ANC≥5.0×109·L-1. Safety, efficacy and pharmacokinetics were analyzed. Results: The main pharmacokinetic parameters of PEG-rhG-CSF after three single dose injection were as follows:t1/2 was (88. 6 ±52) , (56. 9 ±11) , (71.7 ±23), (73.9 ±23), (77.4±14) h; CL_F was: ( 26.7 ±21), (19.7 ±5), (19.5 ±9), (21.6 ±9) , (12.4 ±4) mL·h-1·kg-1; AUC0~1, was (473.2 ±380), (1 009.8 ±245), (1 844.8 ±1 111), (2 342.2 ± 1 029) , (5 332.6 ±2 120) ng·h·mL-1. There was not detected G-CSF antibody in this study, The mean ANC nadirs was 3.43×109, 3.0×109, 2.96×109 and 3.0×109×L-1 in cycle 2, which was higher than those in cycle 1 and cycle 3. Conclusion: The pharmacokinetics of YPEG-rHuG-CSF was a linear profile between 20~45 μg·kg-1 and was a non-linear profile at 60 μg· kg-1 . It can effectively prevent neutropenia by once-per-cycle administration.%目的:在化疗后引起的中性粒细胞减少症的肿瘤患者中评价Y型聚乙二醇重组人粒细胞集落刺激因子(YPEG-rHuG-CSF)注射液的Ⅰ期临床药代动力学和药效学.方法:入组肿瘤患者接受剂量相同的3个周期化疗方案,第1周期为筛选周期,对于绝对中性粒细胞计数(ANC) ＜1.5×109·L-1的患者,第2周期化疗药物给药结束后48 h皮下注射1次5个不同剂量[10(预试验组),20,30,45和60μg· kg-1]的YPEG-rHuG-CSF.第3周期为对照周期,于化疗药物开始给药后48 h,随机每日1次皮下注射150或300 μg对照药物(特尔津(R))直到ANC≥5.0×109·L-1.分析YPEG-rHuG-CSF的安全性、有效性及药代动力学特征.结果:共入组30例患者,5个YPEG-rHuG-CSF剂量组的主要药代动力学参数如下:t1/2分别为(88.6±52),(56.9±11),(71.7±23),(73.9±23)和(77.4±14) h;CL_F分别为:(26.7±21),(19.7±5),(19.5±9),(21.6±9)和(12.4±4) mL·h-1·kg-1；AUC0-t分别为(473.2±380),(1 009.8±245),(1 844.8±1111),(2 342.2±1 029)和(5 332.6±2 120) ng·h·mL-1.本研究在试验药物给药前及给药20 d内未检测到G-CSF抗体.第2周期除预试验组外4个剂量组的ANC最低点均值分别为3.43×109,3.0×109,2.96×109和3.0 ×109·L-1,均比第1和第3周期有所提高.结论:给药剂量为20 ～45 μg·kg-1时,药物在人体内呈现线性药代动力学特征；在给药剂量增加到60 μg· kg-1时,药物在人体内呈现非线性药代动力学特征.YPEG-rHuG-CSF在体内维持药效时间长,1次注射可有效预防中性粒细胞减少症.