【作者】 张坦； 祖丽安； 王茜； 吴全睿； 臧彦楠； 陈适； 王梅； 汪进； 陶涛； 廖庆平； 郑青山； 栗占国； 方翼；

【Author】 ZHANG Tan;ZU Li-an;WANG Qian;WU Quan-rui;ZANG Yan-nan;CHEN Shi;WANG Mei;WANG Jin;TAO Tao;LIAO Qing-ping;ZHENG Qing-shan;LI Zhan-guo;FANG Yi;Department of Pharmacy;Peking University People’s Hospital;Department of Pharmacy,School of Pharmaceutical,Peking University;Comprehensive chemotherapy ward;Peking University People’s Hospital;Department of Medical,Biotechnology Iinstitute of Shanghai Sunshine;Department of Pharmacy, Beijing Anding Hospital, Capital Medical University;Department of Rheumatology and Immunology,Peking University People’s Hospital;The Center for Drug Clinical Research, Shanghai University of TCM;

【机构】 北京大学人民医院药剂科； 北京大学医学部药学院； 北京大学人民医院综合化疗病房； 上海三生国健生物技术研究院医学部； 首都医科大学附属北京安定医院药剂科； 北京大学人民医院风湿免疫科； 上海中医药大学药物临床研究中心；

【摘要】 目的研究人源化抗人TNF-α单克隆抗体在中国健康成年志愿者中单次皮下注射后,产生的抗药性抗体(ADA)对其药代动力学的影响。方法共纳入60例健康志愿者,分为6个递增剂量组,每组受试者单次腹部皮下注射人源化抗人TNF-α单克隆抗体5 mg、15 mg、30 mg、50 mg、75 mg或100 mg,测定给药前、给药后第4、12、24、36、48、60、72、96、120、144、168、216、264、312、360、408、456、504、576和672小时的血药浓度,以及给药前、给药后168、360、504和672小时的ADA。结果 5 mg～100 mg剂量组ADA阳性率分别为100%,100%,100%,80%,90%和70%,总体阳性率高达88%。检出ADA后,ADA+者的血药浓度迅速下降,其平均血药浓度均低于ADA-者,差异具有统计学意义(P <0. 05)。ADA+者半衰期(t1/2)显著低于ADA-者,75 mg～100 mg组ADA+者的清除率(CL)高于ADA-者。结论注射用人源化抗人TNF-α单克隆抗体的ADA阳性率较高,血药浓度、t1/2的降低,CL的升高可能与ADA的产生有关。更多还原

【Abstract】 Objective To assess the effect of anti-drug antibody on pharmacokinetics after single subcutaneous use of humanized anti-human TNF-α monoclonal antibody in healthy subjects. Methods Sixty subjects were equally divided into six dosage groups to receive 5 mg, 15 mg, 30 mg, 50 mg, 75 mg or 100 mg humanized anti-human TNF-α monoclonal antibody. The serum concentration was evaluated pre-dose and at 4, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 216, 264, 312, 360, 408, 456, 504, 576 and 672 hours after dose. The anti-drug antibodies were detected pre-dose and at 168, 360, 504 and 672 hours after dose. Results The ADA positive rates of groups 5 mg, 15 mg, 30 mg, 50 mg, 75 mg and 100 mg were 100%, 100%, 100%, 80%, 90% and 70%, respectively. The overall ADA-positive rate was as high as 88%. The serum concentration of ADA-positive subjects decreased rapidly, and was lower than that of ADA-negative subjects(P < 0.05). The half-life(t1/2) of ADA-positive subjects were significantly lower than those of ADA-negative subjects. In 75 mg and 100 mg groups, the clearance rates(CL) of ADA-positive subjects were higher than that of ADA-negative subjects. Conclusion The incidence of ADA in humanized anti-human TNF-α monoclonal antibody is high, and the decrease of serum concentration, t1/2 and the increase of CL is related to the production of ADA.更多还原