王海荣,范明源,项宗尚,宋紫辉,胡晓丞,张春云,蔡永明,张宗鹏.重组人胰岛素注射液临床前生物相似性评价研究[J].药物评价研究,2016,():
重组人胰岛素注射液临床前生物相似性评价研究
Pre-clinical bio-similarity evaluation of Recombinant Human Insulin R
投稿时间:2015-09-17  
DOI:
中文关键词:  胰岛素;安全性评价;免疫原性;Beagle犬;生物类似物
英文关键词:Insulin; Toxicology; Immunogenicity; Beagle canine; Bio-similar
基金项目:天津创新药物安全评价技术平台(2013ZX09302301)
作者单位
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 
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中文摘要:
      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。
英文摘要:
      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 toxicological study was considered to be 0.5 IU/kg, and with no anti-Insulin R antibody detected, showing a great biosimilarity with Humulin R.
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