国产与进口重组人胰岛素注射液Beagle犬皮下注射的生物等效性研究

Bioequivalence of domestic and imported recombinant human insulin injections after sc administration in Beagle dogs

目的以美国礼来公司重组人胰岛素注射液(优泌林R,Humulin R)为对照品,评价国产重组人胰岛素注射液(Insulin R)的相对生物利用度和生物等效性。方法采用自身随机交叉给药方案,12只健康Beagle犬分别sc同剂量Insulin R和Humulin R,按设计采集6 h内动态血标本。采用罗氏血糖仪与检测血药浓度同步测定动物血糖水平;放射免疫分析(RIA)法检测血药浓度;试验数据采用DAS 3.0药动学程序拟合计算参数,并进行生物等效性分析。结果 Beagle犬自身交叉sc Insulin R和Humulin R 0.5 U/kg后的血浆最低葡萄糖浓度(Cmin)分别为(1.6±0.4)、(1.6±0.2)mmol/L;达到最低浓度所需时间(tmin)分别为(1.0±0.5)、(1.1±0.6)h。Insulin R和Humulin R的主要药动学参数均值分别为:达峰时间(tmax)为(0.43±0.21)、(0.42±0.09)h;峰浓度(Cmax)为(203.2±63.3)、(193.5±63.1)μU/m L;药时曲线下面积(AUC0-6 h)为(281.2±47.5)、(266.6±62.5)μU/(m L·h);受试药Insulin R相对于对照药Humulin R的相对生物利用度为(109.4±25.5)%。结论两种重组人胰岛素注射剂在健康Beagle犬体内具有生物等效性。

Objective To assess the pharmacokinetic and bioequivalence of two formulations of recombinant human insulin injection, using locally manufactured Insulin R as test and Humulin R（Eli Lilly and Company） as reference. Methods Twelve Beagle dogs were assigned into two groups in which the dogs were sc given Insulin R and Humulin R at the dose of 0.5 U/kg according to a randomized two-phase crossover. The plasma concentration of Insulin R and Humulin R at 6 h intervals was determined using radioimmunoassay（RIA） method with the time course of changes in blood glucose level monitored. The pharmacokinetic parameters were calculated by DAS 3.0 software. Results Beagle dogs were treated with Insulin R and Humulin R following single sc administration at the dose of 0.5 U/kg, and the minimum blood glucose levels（Cmin） were（1.6 ± 0.4） and（1.6 ± 0.2） mmol/L, while time to reach minimum blood glucose level（tmin） was（1.0 ± 0.5） and（1.1 ± 0.6） h, respectively. The main pharmacokinetics parameters of Insulin R and Humulin R were as follows： time to reach peak concentration（tmax） was（0.43 ± 0.21） and（0.42 ± 0.09） h; peak concentration（Cmax） was（203.2 ± 63.3） and（193.5 ± 63.1） μU/m L; area under the concentration- time curve（AUC） was（281.2 ± 47.5） and（266.6 ± 62.5） μU/（m L·h）, respectively. The relative bioavailability for Insulin R was（109.4 ± 25.5）% compared to that for Humulin R following single sc administration. Conclusion Test and reference drugs meet the regulatory criteria for the pharmacokinetic equivalence, thus Insulin R and Humulin R are bioequivalent.