精蛋白重组人胰岛素注射液(预混30/70)与优泌林70/30在Beagle犬体内的生物等效性研究

Bioequivalence of Isophane Protamine recombinant human insulin( pre-mixed 30/70) and Humulin~ 70/30 injection after sc administration in Beagle dogs

目的:研究国产的精蛋白重组人胰岛素(预混30/70)注射液(试验制剂)与美国礼来公司已上市的精蛋白锌重组人胰岛素混合注射液(商品名:优泌林~70/30,参比制剂)在Beagle犬体内的药动学及生物等效性。方法:采用单剂量试验制剂和参比制剂自身双交叉给药方案,12只健康Beagle犬分别皮下注射同剂量精蛋白重组人胰岛素混合注射液和优泌林~70/30,给药后不同时间经静脉采集血浆标本同时采用罗氏血糖仪同步测定动物血糖水平;放射免疫分析(RIA)法检测血药浓度;血药浓度数据用DAS2.0药代动力学软件拟合计算参数,并进行生物等效性分析;血糖数据用成对t检验进行分析。结果:12只Beagle犬交叉皮下注射5U/只试验制剂与参比制剂后,主要药代参数分别是:平均t_(1/2)为(2.51±1.83)h和(2.48±1.33)h;平均C_(max)为(88.01±21.42)μU/m L和(100.52±36.71)μU/m L;平均T_(max)为(1.40±0.88)h和(1.29±0.45)h;平均AUC_(0-t)为(365.5±82.4)μU·mL^(-1)·h^(-1)和(372.9±86.5)μU·mL^(-1)·h^(-1)。血浆最低葡萄糖浓度(C_(min))分别为(1.59±0.38)mmol/L和(1.64±0.43)mmol/L,达到最低浓度所需时间(T_(min))分别为(2.38±1.35)h和(2.13±0.86)h。结论:精蛋白重组人胰岛素(预混30/70)与优泌林~70/30在Beagle犬体内具有生物等效性。

AIM： To investigate the pharmacokinetic and bioequivalence of the domestic（ Isophane Protamine recombinant human insulin,premixed 30 /70,test preparation） and the reference preparation named Humulin70 /30（ Protamine Zinc recombinant human insulin,Eli Lilly and Company,USA） in Beagle dogs. METHODS： Twelve Beagle dogs were assigned into two groups and the two groups were separately singlely given with Isophane Protamine recombinant human insulin and HumulinNPH in the same dose in sc injection method according to a randomized two-phase crossover. The plasma were sampled at different time point after subcutaneous administration and the blood glucose levels were determined by Roche Glucose meter synchronously. The radioimmunoassay（ RIA）method was used to determine the concentration of blood insulin at the different sample points. The pharmacokinetic parameters were calculated by DAS2. 0 software. RESULTS： Beagle dogs were treated with test preparation and reference preparation following single sc administration at the dose of 5 UI /animal. The main pharmacokinetics parameters of test preparation and reference preparation were as follows： The elimination half-life（ t_（1/2）） were（ 2. 51± 1. 83） and（ 2. 48 ± 1. 33） h,the peak concentration（ C_（max））（ 88. 01 ± 21. 42） and（ 100. 52 ±36. 71） μU/mL,the peak time（ T_（max））（ 1. 40 ±0. 88） and（ 1. 29 ± 0. 45） hand the area under the concentration-time curve（ AUC_（0- t））（ 365. 5 ±82. 4） and（ 372. 9 ± 86. 5） μU·mL（-1）·h（-1）,respectively. What＇s more,the minimum blood glucose levels（ C_（min）） of the tested and the referenced were（ 1. 59 ± 0. 38） and（ 1. 64 ± 0. 43） mmol/L separately,and the T_（min）（ time to reach minimum blood glucose level） were（ 2. 38 ± 1. 35） and（ 2. 13 ±0. 86） h,respectively. CONCLUSION： The results showed that the test and the reference preparation meet the regulatory criteria for the pharmacokinetic equivalence. Therefore, Isophane Protamine recombinant human insulin（ pre-mixed 30 /70）（ the tested one） and Humulin70 /30（ the commercially available） were bioequivalent in the therapy effect.