目的 研究注射用重組人成纖維細(xì)胞生長(zhǎng)因子-21（FGF-21）在食蟹猴體內(nèi)單次和多次皮下給藥后的藥代動(dòng)力學(xué)特征。方法 采用隨機(jī)、平行和劑量遞增設(shè)計(jì)，18只食蟹猴分別單次sc150、300和600 μg/kg的FGF-21或多次sc 300 μg/kg的FGF-21，按設(shè)計(jì)采集動(dòng)態(tài)血清樣本。采用雙抗體夾心ELISA法檢測(cè)血清中藥物濃度的動(dòng)態(tài)變化，采用DAS 3.2.4藥動(dòng)程序擬合并計(jì)算藥動(dòng)參數(shù)。結(jié)果 食蟹猴單次sc FGF-21后，各劑量組峰濃度C_max和藥時(shí)曲線下面積AUC_（0-24h）、AUC_（0-∞）均隨給藥劑量的增加而增大，C_max、AUC_（0-24h）和AUC_（0-∞）三者均與劑量呈線性相關(guān)，各劑量組t_1/2Z、T_max、CL_z和V_z均較為一致。與單次給藥相比，食蟹猴多次sc給藥后的t_1/2z有所延長(zhǎng)但其他主要PK參數(shù)（T_max、V_z和CL_z等）均較為一致，多次給藥后，體內(nèi)藥物無(wú)蓄積傾向。結(jié)論 食蟹猴單次sc FGF-21后，在150~600 μg/kg劑量范圍內(nèi)呈現(xiàn)線性動(dòng)力學(xué)特征。單次與多次sc給予FGF-21后，兩者的PK行為特征基本一致，無(wú)明顯藥物蓄積。

Objective The pharmacokinetic profile of recombinant human fibroblastgrowth factor-21(FGF-21) for injection after single and multiple subcutaneous administration in cynomolgus monkeys was studied. Methods 18 cynomolgus monkeys were administered subcutaneously at single dose of 150, 300, 600 μg/kg FGF-21 or multiple dose of 300 μg/kg in a randomized design, parallel and dose-escalation study. ELISA method was developed to determine the dynamic changes of drug concentration in serum, and pharmacokinetic parameters were calculated by using DAS 3.2.4 pharmacokinetics program. Results Pharmacokinetic parameters in cynomolgus monkeys between different single dose groups are as follows:C_max, AUC_{(0-24 h)} and AUC_(0-∞) were positively proportional linear related with increasing dose.t_1/2Z, T_max, CL_z, and V_z were all consistent in each dose groups. Compared with single administration, the t_1/2z of cynomolgus monkeys was prolonged after multiple administrations, but other major PK parameters (T_max, V_z, CL_z) were consistent. After repeated administration, there was no accumulation tendency of drugs in body. Conclusion FGF-21 administered subcutaneously at single dose of 150-600 μg/kg in cynomolgus monkeys exhibits linear pharmacokinetics. The characteristics of pharmacokinetics are basically consistent with single and multiple dose of 300 μg/kg FGF-21, indicating that no significant drug accumulation was ovserved.

新藥臨床前藥物代謝動(dòng)力學(xué)技術(shù)平臺(tái)建設(shè)（2011zx09102-004-03）