本文關(guān)鍵詞：聚乙二醇化重組人胰島素注射液Beagle犬毒動(dòng)學(xué)研究　出處：《藥物評價(jià)研究》2016年06期 　論文類型：期刊論文

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【摘要】：目的研究毒性劑量暴露下聚乙二醇化重組人胰島素注射液(PEG-Det)的毒動(dòng)學(xué)(TK),以評價(jià)系統(tǒng)暴露與劑量、時(shí)間及毒性結(jié)果之間的關(guān)系,通過重復(fù)給藥分析藥物在體內(nèi)是否存在蓄積及代謝方式是否改變等特性。方法 32只健康Beagle犬隨機(jī)分為4組,每組8只,雌雄各半,分別sc低、中、高劑量(37.5、75.0、150.0μg/kg)PEG-Det及溶媒,每周給藥2次,重復(fù)給藥9個(gè)月。分別于首次(d1)、中期(d89)和末期(d260)給藥后采用放射免疫分析(RIA)法檢測不同時(shí)間血藥濃度,采用羅氏血糖儀同步測定動(dòng)物血糖水平。試驗(yàn)數(shù)據(jù)采用DAS 3.0藥動(dòng)程序擬合分析并計(jì)算TK參數(shù)。結(jié)果各劑量組動(dòng)物sc給藥后,隨血藥濃度升高伴隨血糖降低,且與給藥劑量呈正相關(guān);隨給藥頻率增加,血糖降低幅度減小;單次和多次給藥后,PEG-Det的Cmax和AUC與劑量均呈正相關(guān);隨給藥頻率增加,各劑量組的C_(max)和AUC_(ss)降低,且給藥末期(9個(gè)月)的蓄積指數(shù)(RC_(max)和R_(AUC))均小于1;各劑量組在給藥不同階段的消除半衰期t1/2z為20~30 h;達(dá)峰時(shí)間T_(max)和清除率CLz/F均在一定范圍內(nèi)波動(dòng),不與劑量相關(guān)。結(jié)論 Beagle犬重復(fù)sc給予PEG-Det 37.5、75.0、150.0μg/kg,隨給藥劑量增加,藥物暴露量增大;經(jīng)多次給藥后,血漿中胰島素濃度趨于平穩(wěn),體內(nèi)無藥物蓄積;且血糖降低幅度減少,在維持有效濃度和藥效的基礎(chǔ)上,降低了由低血糖帶來的安全性風(fēng)險(xiǎn)。
[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.
【作者單位】： 天津藥物研究院新藥評價(jià)有限公司;
【基金】：天津創(chuàng)新藥物安全評價(jià)技術(shù)平臺(2013ZX09302301)
【分類號】：R965
【正文快照】： 目前,糖尿病已成為威脅人類健康的第三大重大疾病,僅次于心腦血管疾病和腫瘤[1-2]。隨著近年來其發(fā)展趨勢的年輕化和大眾化,新型胰島素類似物的開發(fā)逐漸成為眾多研究者關(guān)注的焦點(diǎn)[3-6]。聚乙二醇化重組人胰島素注射液(PEG-Det)屬生物工程一類新藥,是通過對地特胰島素(Det)聚乙

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