聚乙二醇化重组人胰岛素注射液Beagle犬毒动学研究

发布时间：2018-01-06 20:32

本文关键词：聚乙二醇化重组人胰岛素注射液Beagle犬毒动学研究　出处：《药物评价研究》2016年06期 　论文类型：期刊论文

【摘要】：目的研究毒性剂量暴露下聚乙二醇化重组人胰岛素注射液(PEG-Det)的毒动学(TK),以评价系统暴露与剂量、时间及毒性结果之间的关系,通过重复给药分析药物在体内是否存在蓄积及代谢方式是否改变等特性。方法 32只健康Beagle犬随机分为4组,每组8只,雌雄各半,分别sc低、中、高剂量(37.5、75.0、150.0μg/kg)PEG-Det及溶媒,每周给药2次,重复给药9个月。分别于首次(d1)、中期(d89)和末期(d260)给药后采用放射免疫分析(RIA)法检测不同时间血药浓度,采用罗氏血糖仪同步测定动物血糖水平。试验数据采用DAS 3.0药动程序拟合分析并计算TK参数。结果各剂量组动物sc给药后,随血药浓度升高伴随血糖降低,且与给药剂量呈正相关;随给药频率增加,血糖降低幅度减小;单次和多次给药后,PEG-Det的Cmax和AUC与剂量均呈正相关;随给药频率增加,各剂量组的C_(max)和AUC_(ss)降低,且给药末期(9个月)的蓄积指数(RC_(max)和R_(AUC))均小于1;各剂量组在给药不同阶段的消除半衰期t1/2z为20~30 h;达峰时间T_(max)和清除率CLz/F均在一定范围内波动,不与剂量相关。结论 Beagle犬重复sc给予PEG-Det 37.5、75.0、150.0μg/kg,随给药剂量增加,药物暴露量增大;经多次给药后,血浆中胰岛素浓度趋于平稳,体内无药物蓄积;且血糖降低幅度减少,在维持有效浓度和药效的基础上,降低了由低血糖带来的安全性风险。
[Abstract]:Objective to study the toxicokinetics of PEG-Dett in PEG-Dett exposed to toxic dose, and to evaluate the relationship between systemic exposure and dose, time and toxicity. Methods 32 healthy Beagle dogs were randomly divided into 4 groups, 8 in each group, half male and half female, with low SC. PEG-Det and solute were given twice a week and repeated for 9 months, respectively, on the first day 1 (n = 1). The dose of PEG-Det was 150.0 渭 g / kg of 75.0 渭 g / kg of 77.5 渭 g 路kg -1 路kg ~ (-1) 渭 g 路kg ~ (-1) 路kg ~ (-1). After administration, RIA was used to detect the blood concentration at different times. The blood glucose level of animals was measured by Roche blood glucose analyzer. The experimental data were analyzed by DAS 3.0 pharmacokinetic program and TK parameters were calculated. With the increase of blood concentration, blood glucose decreased, and there was a positive correlation with the dosage of the drug. The decrease of blood glucose decreased with the increase of administration frequency. The Cmax and AUC of PEG-Det were positively correlated with the dose of PEG-Det. With the increase of the frequency of administration, the C _ S _ (max) and AUC _ S) of each dose group decreased, and the accumulative index (RCX _ max) and R _ (C) AUC _ (n) of each dose group were less than 1 at the end of the drug administration (9 months); The elimination half-life t _ (1 / 2) z of each dose group at different stages of administration was 200.30 h. Peak time) and clearance rate (CLz/F) fluctuated in a certain range and were not correlated with dose. Conclusion Beagle dogs were given PEG-Det 37.5 by repeated sc. 75.0 渭 g / kg, with the increase of dosage, the amount of drug exposure increased; After repeated administration, the concentration of insulin in plasma tended to be stable, and there was no accumulation of drugs in the body. The decrease of blood glucose decreased the safety risk caused by hypoglycemia on the basis of maintaining effective concentration and efficacy.
【作者单位】：天津药物研究院新药评价有限公司;
【基金】：天津创新药物安全评价技术平台(2013ZX09302301)
【分类号】：R965
【正文快照】： 目前,糖尿病已成为威胁人类健康的第三大重大疾病,仅次于心脑血管疾病和肿瘤[1-2]。随着近年来其发展趋势的年轻化和大众化,新型胰岛素类似物的开发逐渐成为众多研究者关注的焦点[3-6]。聚乙二醇化重组人胰岛素注射液(PEG-Det)属生物工程一类新药,是通过对地特胰岛素(Det)聚乙

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