重组人胰岛素注射液临床前生物相似性评价研究.PDFVIP

重组人胰岛素注射液临床前生物相似性评价研究 王海荣，范明源，项宗尚，宋紫辉，胡晓丞，张春云，蔡永明，张宗鹏* 天津药物研究院新药评价有限公司，天津 300301 摘要：目的通过Beagle 犬长期给药毒性试验及免疫原性试验，评价重组人胰岛素注射液（Insulin R ）与原研药 （Humulin R ）的 生物相似性。方法进行Beagle 犬scInsulin R30 d 停药14 d 长期给药毒性试验，Insulin R 剂量为0.5、1.0、1.5 IU/kg，Humulin R 剂量为1.5 IU/kg，检测指标包括一般状况、进食量、体温、心电图、血液学、凝血、血清生化、电解质及尿液等，于给药 期结束及停药期结束分两次剖杀动物，测定主要脏器的脏器系数并进行常规病理组织学检查；ELISA 法检测Beagle 犬血清 的免疫原性。结果 Beagle 犬重复sc Insulin R30 d 毒性试验中，中、高剂量组部分动物出现食欲降低、食量减少，高剂量1 只雄性动物出现流涎、站立不稳、心率加速、抽搐等低血糖症状，中、高剂量组动物心率增加；原研药组与Insulin R 高剂 量组毒性反应相当；Beagle 犬给予Insulin R 30 d 未检测到抗药抗体。结论 Beagle 犬sc Insulin R30 d 时的最大无毒反应剂量 为0.5 IU/kg，相当于临床等效剂量的0.5 倍，且未产生抗药抗体，与Humulin R 具有较好的临床前生物相似性。 关键词：胰岛素；安全性评价；免疫原性；Beagle 犬；生物类似物 中图分类号：R 文献标志码：A 文章编号：1674 - 6376 (20 16) 0 1 - 0 - 06 DOI: 10.7501/j.issn.1674-6376.2016.01. Pre-clinical bio-similarity evaluation of Recombinant Human Insulin R WANG Hai-rong, FAN Ming-yuan, XIANG Zong-shang, SONG Zi-hui, HU Xiao-cheng, ZHANG Chun-yun, CAI Yong-ming, ZHANG Zong-peng TJIPR Drug Assessment Co. Ltd, Tianjin 300301, China Abstract:ObjectiveThe purpose of this article is to investigate the bio-similarity of Insulin R via repeated-dose toxicity study and immunogenicity study. MethodsIn this 30-day subcutaneous injection toxicity study in Beagle canines, bio-similarity of Insulin R was evaluated in doses of 0.5, 1.0 and 1.5 IU/kg via clinical observation, food consumption, clinical pathology, histo-pathology and immunogenicity test, with vehicle and Humulin R (1.5 IU/kg) groups as controls. ResultsSymptoms of food consumption reduction, and vomits were observed in high and middle-dose groups; and one male animal in high dose group had salivation, tachycardia and convulsion on the first 8 days. Similar toxic reactions were found in Humulin R group. No anti-Insulin R or anti-Humulin R antibody was detected. ConclusionThe NOAEL of Insulin R in this Beagle dog repeated-dose