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[摘要]
目的 研究注射用重组人成纤维细胞生长因子-21(FGF-21)在食蟹猴体内单次和多次皮下给药后的药代动力学特征。方法 采用随机、平行和剂量递增设计,18只食蟹猴分别单次sc150、300和600 μg/kg的FGF-21或多次sc 300 μg/kg的FGF-21,按设计采集动态血清样本。采用双抗体夹心ELISA法检测血清中药物浓度的动态变化,采用DAS 3.2.4药动程序拟合并计算药动参数。结果 食蟹猴单次sc FGF-21后,各剂量组峰浓度Cmax和药时曲线下面积AUC(0-24h)、AUC(0-∞)均随给药剂量的增加而增大,Cmax、AUC(0-24h)和AUC(0-∞)三者均与剂量呈线性相关,各剂量组t1/2Z、Tmax、CLz和Vz均较为一致。与单次给药相比,食蟹猴多次sc给药后的t1/2z有所延长但其他主要PK参数(Tmax、Vz和CLz等)均较为一致,多次给药后,体内药物无蓄积倾向。结论 食蟹猴单次sc FGF-21后,在150~600 μg/kg剂量范围内呈现线性动力学特征。单次与多次sc给予FGF-21后,两者的PK行为特征基本一致,无明显药物蓄积。
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[Abstract]
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:Cmax, AUC(0-24 h) and AUC(0-∞) were positively proportional linear related with increasing dose.t1/2Z, Tmax, CLz, and Vz were all consistent in each dose groups. Compared with single administration, the t1/2z of cynomolgus monkeys was prolonged after multiple administrations, but other major PK parameters (Tmax, Vz, CLz) 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.
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[基金项目]
新药临床前药物代谢动力学技术平台建设(2011zx09102-004-03)