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）的毒動學(xué)（TK），以評價系統(tǒng)暴露與劑量、時間及毒性結(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、150.0 μg/kg）PEG-Det及溶媒，每周給藥2次，重復(fù)給藥9個月。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）法檢測不同時間血藥濃度，采用羅氏血糖儀同步測定動物血糖水平。試驗(yàn)數(shù)據(jù)采用DAS 3.0藥動程序擬合分析并計算TK參數(shù)。結(jié)果 各劑量組動物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?。粏未魏投啻谓o藥后，PEG-Det的C_max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個月）的蓄積指數(shù)（R_Cmax和R_AUC）均小于1；各劑量組在給藥不同階段的消除半衰期t_1/2z為20~30 h；達(dá)峰時間T_max和清除率CL_z/F均在一定范圍內(nèi)波動，不與劑量相關(guān)。結(jié)論 Beagle犬重復(fù)sc給予PEG-Det 37.5、75.0、150.0 μg/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。

Objective To study toxicokinetics of pegylated recombinant human insulin injection (PEG-Det) at the toxic dose, and to evaluate the relationship between systemic exposure and dose, time or toxicity outcomes. The existence of drug accumulation and the change of drug metabolism characteristics in vivo are explored by multiple administration of the drug. Methods Tatolly 32 healthy Beagle's dogs were randomly divided into four groups, including low, medium and high dose (37.5, 75.0 and 150 μg/kg) groups of PEG-Det, and vehicle control group. Each group included 8 Beagle's dogs, with male and female animals each half. All animals were sc administered twice a week with continuous dosing for 9 months. The plasma concentration of PEG-Det in period of first day (d1), mid-term (d89) and late-term (d260) dosing was determined using a radioimmunoassay (RIA) method. Meanwhile, the blood glucose level was monitored using a Roche blood glucose meter. The toxicokinetic parameters were calculated by DAS 3.0 software. Results After drug administration, the blood glucose which was positively correlated with the dose decreased along with elevated plasma concentration of PEG-Det. But with increasing of dosing times, the reduction amplitude of blood glucose diminished. The C_max and AUC of PEG-Det were both positively correlated with the dose after single or multiple drug administration. And the C_max and AUC_ss of different dose groups reduced with increasing of dosing times. The accumulation indexes (R_Cmax and R_AUC) were both less than one after nine months dosing, indicating that there was no drug accumulation in vivo of Beagle's dog. The mean elimination half-life t_1/2z ranged from 20 to 30 h, which displayed its characteristics of long-lasting effect. The peak concentration arrival time T_max and clearance CL_z/F fluctuated within a certain range, and were independent of dose. Conclusion Beagle's dogs are sc treated with PEG-Det at different doses of 37.5, 75.0, and 150.0 μg/kg for 9 months. With the increase of dose, drug exposure could increase. After multiple dosing, the plasma concentration of insulin trends to be stable. There is no drug accumulation in vivo. The reduction amplitude of blood glucose reduces, which lowers the safety risks of hypoglycemia on the basis of maintaining the effective concentration and efficacy.

天津創(chuàng)新藥物安全評價技術(shù)平臺（2013ZX09302301）