采用正葡萄糖钳夹技术评价联邦制药生产的门冬胰岛素药代动力学、药效动力学及生物等效性

The Pharmacokinetics,Pharmacodynamics and Bioequivalence of Insulin Aspart Produced by the United Laboratories Evaluated by Euglycemic Clamp Study

目的在中国健康受试者中,对联邦制药公司生产的速效胰岛素--门冬胰岛素(作为受试制剂)进行人体药代动力学、药效动力学研究,并以丹麦诺和诺德公司生产的门冬胰岛素(商品名:诺和锐■)为参比制剂,评价两种制剂的生物等效性。方法招募24例男性健康受试者,对受试者采用自身前后对照、单次剂量、随机、双交叉研究。受试者分别在2个试验日接受试验观察,2次试验间隔时间为7~10 d。受试者按随机数字表法随机分为A、B两组,A组第1次用受试制剂门冬胰岛素,第2次用参比制剂诺和锐■;B组则与A组给药顺序相反。采用正常血糖葡萄糖钳夹技术进行药代动力学和药效动力学研究。结果受试制剂门冬胰岛素降糖作用的相对生物利用度(反映降糖作用的有效性)为98.3%±18.8%,反映血药浓度的相对生物利用度为97.3%±8.3%。药代动力学参数血胰岛素峰浓度和0~10 h的血胰岛素浓度曲线下面积90%可信区间分别为88.8%~106%(等效范围70%~143%)和94.0%~100%(等效范围80%~125%),药效动力学参数最高葡萄糖输注率、0~10 h葡萄糖输注率曲线下面积90%可信区间分别为95.5%~113%(等效范围70%~143%)和89.9%~104%(等效范围80%~125%),两种制剂具有生物等效性。试验中1例受试者出现无症状高尿酸血症,余受试者试验前、后各安全性指标均无临床意义的异常值。试验过程中未见有低血糖、过敏反应及注射局部不良反应发生。结论受试制剂联邦制药的门冬胰岛素和参比制剂诺和锐■具有生物等效性。

Objective To investigate the pharmacokinetics(PK) and pharmacodynamics(PD) of a rapid-acting insulin analog-insulin aspart(the tested formulation) which was manufactured by The United Laboratories and to evaluate the bioequiavailability to the reference formulation(NovoRapid■) produced by Novo Nordisk in Chinese healthy volunteers. Methods A total of 24 male healthy volunteers were recruited from February to April 2016 to participant in this before-after, single dose, and randomized crossover study. And the experimental observation was conducted on 2 test days respectively with a between-period from 7 to10 d. According to a random number table, the volunteers were divided into group A or B, group A was administrated with tested insulin aspart(IAsp) for the first time and reference NovoRapid■ for the second time and group B had the revered order differed from group A. The PK/PD of these insulin analogs were estimated by euglycemic clamp study. Results The relative biological effectiveness(reflecting gloucoselowing effect) and bioavailability on behalf of plasma-drug concentration were 98.3±18.8% and 97.3%±8.3% respectively.For PK parameters, the 90% confidence interval(CI) of peak plasma insulin concentration(Cmax) and area under the curve of insulin aspart concentration from 0 to 10 hours(AUCIAsp, 0-10 h) of IAsp were 88.8%-106%(equivalent range 70%-143%)and 94.0%-100%(equivalent range 80%-125%) respectively;for PD parameters, the 90%CI of the maximum glucose infusion rate(GIRmax) and AUCGIR, 0-10 h were 95.5%-113%(equivalent range 70%-143%) and 89.9%-104%(equivalent range 80%-125%) respectively, which indicated that IAsp and NovoRapid■ was bioequivalent. One of the subjects discovered hyperuricemia without clinical symptoms and the rest had no clinically significant abnormalities in the safety indexes before and after the tests. No hypoglycemic events, allergic reactions, or local injection adverse reaction occurred in this trial. Conclusion The tested IAsp has comparable relative bioavailability to the reference NovoRapid■.