目的 通過Beagle犬長期給藥毒性試驗及免疫原性試驗,評價重組人胰島素注射液(Insulin R)與原研藥(Humulin R)的生物相似性。方法 進行Beagle犬scInsulin R 30 d停藥14 d長期給藥毒性試驗,Insulin R劑量為0.5、1.0、1.5 IU/kg,Humulin R劑量為1.5 IU/kg,檢測指標包括一般狀況、進食量、體溫、心電圖、血液學、凝血、血清生化、電解質及尿液等,于給藥期結束及停藥期結束分兩次剖殺動物,測定主要臟器的臟器系數并進行常規(guī)病理組織學檢查;ELISA法檢測Beagle犬血清的免疫原性。結果 Beagle犬重復sc Insulin R 30 d毒性試驗中,中、高劑量組部分動物出現食欲降低、食量減少,高劑量1只雄性動物出現流涎、站立不穩(wěn)、心率加速、抽搐等低血糖癥狀,中、高劑量組動物心率增加;原研藥組與InsulinR高劑量組毒性反應相當;Beagle犬給予Insulin R 30 d未檢測到抗藥抗體。結論 Beagle犬sc Insulin R 30 d時的最大無毒反應劑量為0.5 IU/kg,相當于臨床等效劑量的0.5倍,且未產生抗藥抗體,與Humulin R具有較好的臨床前生物相似性。

Objective To investigate the bio-similarity of Insulin R via repeated-dose toxicity study and immunogenicity study. Methods In this 30-day sc injection toxicity study in Beagle's dogs, the 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, histopathology, and immunogenicity test, with vehicle and Humulin R (1.5 IU/kg) groups as controls. Results Symptoms of food consumption reduction, and vomits were observed in highand mid-dose groups; and one male animal in high-dose group had salivation, tachycardia, and convulsion on the first 8 d. Similar toxic reactions were found in Humulin R group. No anti-Insulin R or anti-Humulin R antibody was detected. Conclusion The NOAEL of Insulin R in this Beagle's 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.

天津創(chuàng)新藥物安全評價技術平臺(2013ZX09302301)